Cyclic compounds useful in the treatment of dyslipidaemia, atherosclerosis and diabetes, pharamaceutical compositions and preparation process

ABSTRACT

The present invention relates to cyclic compounds which are of the class of compounds of formula I wherein X and Y represent an oxygen atom and to processes for preparing such compounds. The compounds are useful in the treatment of dyslipidemia, atherosclerosis, and diabetes.

The present invention relates to cyclic compounds which can be used inthe treatment of dyslipidaemia, atherosclerosis and diabetes, topharmaceutical compositions containing them and to processes forpreparing these compounds.

The invention also relates to the use of these compounds for theproduction of medicinal products intended for the treatment ofdyslipidaemia, atherosclerosis and diabetes.

In most countries, cardiovascular disease remains one of the maindiseases and the main cause of mortality. About a third of men develop amajor cardiovascular disease before the age of 60, women showing a lowerrisk (ratio of 1 to 10). This disease becomes even more prevalent withage (after the age of 65, women become just as vulnerable tocardiovascular disease as men). Vascular diseases such as coronarydisease, cerebrovascular accidents, restenosis and peripheral vasculardisease remain the main cause of mortality and handicap throughout theworld.

Although the diet and the lifestyle can accelerate the development ofcardiovascular diseases, a genetic predisposition leading todyslipidaemia is a significant factor in cardiovascular attacks anddeath.

The development of atherosclerosis appears to be linked mainly todyslipidaemia, which means abnormal levels of lipoproteins in the bloodplasma. This dysfunction is particularly evident in coronary disease,diabetes and obesity.

The concept intended to explain the development of atherosclerosis hasmainly been focused on the metabolism of cholesterol and on themetabolism of triglycerides.

However, since the research studies by Randle et al. (Lancet, 1963,785-789), an original concept has been proposed: a glucose-fatty acidcycle or Randle cycle, which describes regulation of the equilibriumbetween the metabolism of lipids, in terms of triglycerides andcholesterol, and the oxidation of glucose. According to this concept,the inventors have developed an original programme, the aim of which isto find novel compounds which act simultaneously on the metabolism oflipids and glucose.

Fibrates are well-known therapeutic agents with a mechanism of actionvia the “Peroxisome Proliferator Activated Receptors”. These receptorsare the main regulators of lipid metabolism in the liver (PPARαisoform). In the last ten years, thiazolidinediones have been describedas powerful hypoglycaemiant agents in animals and man. It has beenreported that thiazolidinediones are powerful selective activators ofanother form of PPARs: PPARγ (Lehmann et al., J. Biol. Chem., 1995, 270,12953-12956).

The inventors have discovered a novel class of compounds which arepowerful activators of the PPARα and PPARγ isoforms. On account of thisactivity, these compounds have a substantial hypolipidaemiant andhypoglycaemiant effect.

The compounds of the invention correspond to formula I below:

in which

X and Y represent, independently of each other, a methylene group; anoxygen or sulphur atom; or —NR_(a)— in which R_(a) represents a hydrogenatom, a (C₁-C₇)alkyl, (C₆-C₁₀)aryl group or a 3- to 10-memberedheterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, Sand N; the said aryl group and the said heterocycle optionally beingsubstituted with one or more radicals Z as defined below;

R represents a hydrogen atom; a (C₁-C₇)alkyl group; a phthalamido(C₁-C₇) alkyl group; (C₃-C₁₂) cycloalkyl; a group —(CH₂)_(p)—COOR_(b) inwhich p is an integer from 0 to 6 and R_(b) represents a hydrogen atomor a (C₁-C₇)alkyl group; a (C₆-C₁₀)aryl group; a 3- to 10-memberedheterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, Sand N; a (C₆-C₁₀)aryl(C₁-C₇)alkyl group; it being understood that thearyl groups present in R and the said heterocycle are optionallysubstituted with one or more substituents chosen from a radical Z asdefined below and a (C₁-C₇)alkylene chain;

R₁ represents a hydrogen atom; a (C₁-C₇)alkyl group;(C₁-C₇)hydroxyalkyl; a (C₆-C₁₀)aryl group optionally substituted withone or more radicals W as defined below; a group —P(O) (OR₈) (OR₉) inwhich R₈ and R₉ are, independently, a hydrogen atom or a (C₁-C₇)alkylgroup; a group —(CH₂)_(t)—COOR_(c) in which t is an integer from 0 to 6and R_(c) represents a hydrogen atom or a (C₁-C₇)alkyl group; a group—CONR₁₀R₁₁ in which R₁₀ and R₁₁ independently represent a hydrogen atom,a (C₁-C₇)alkyl group, a group R_(d)O—CO—(C₁-C₇)alkyl in which R_(d)represents H or (C₁-C₇)alkyl, or alternatively R₁₀ and R₁₁ together forma —(CH₂) chain in which r is an integer equal to 4, 5 or 6;

R₂ and R₃ independently represent a hydrogen atom; a (C₁-C₇)alkyl group;(C₃-C₁₂)cycloalkyl; (C₆-C₁₀)aryl; (C₆-C₁₀)aryl(C₁-C₇)alkyl; a 3- to10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosenfrom O, N and S; or a fluorenyl group; the said aryl groups present inR₂ or R₃, the said heterocycle and the said fluorenyl optionally beingsubstituted with one or more radicals Z as defined below;

or alternatively R₂ and R₃ together form a chain —(CH₂)_(r1) in which r1is an integer equal to 2, 3, 4 or 5;

or alternatively R₂ and R₃ together form the group (a):

 in which A₁ and A₂ independently represent (C₆-C₁₀)aryl or a 5- to10-membered aromatic heterocycle comprising 1 to 4 endocyclic heteroatoms chosen from N, O and S, the said aryl group and the saidheterocycle optionally bearing, in addition to the substituents R₁₂ andR₁₃, one or more other substituents chosen from the radicals Z asdefined below; and in which R₁₂ and R₁₃ together form a chain

—(CH₂)_(m)—E—(CH₂)_(n)— or —CHR₁₄═CHR₁₅—

in which m and n are, independently, an integer from 0 to 6; Erepresents a bond, O, S, —NR_(e)—, in which R_(e) represents a hydrogenatom or (C₁-C₇)alkyl or alternatively E represents a (C₁-C₇)alkylene or(C₆-C₁₀)arylene chain or a 3- to 10-membered divalent heterocyclicradical comprising 1 to 4 endocyclic hetero atoms chosen from O, N andS; and

R₁₄ and R₁₅ are chosen, independently, from a hydrogen atom,(C₁-C₇)alkyl and (C₆-C10)aryl;

R₄, R₅, R₆ and R₇ independently represent a hydrogen atom; (C₁-C₇)alkyl;(C₆-C10)aryl optionally substituted with one or more radicals Z asdefined below; or a 3- to 10-membered heterocycle comprising 1 to 4endocyclic hetero atoms chosen from O, N and S, the said heterocycleoptionally being substituted with one or more radicals Z as definedbelow;

Z is chosen from a halogen atom; a hydroxyl group; nitro; cyano; phenyl;phenyl (C₁-C₇) alkyl; trifluoromethoxy; (C₁-C₇) alkyl optionallysubstituted with one or more halogen atoms; (C₁-C₇)alkoxy;(C₁-C₇)alkylthio; (C₂-C₇)acylthio; (C₁-C₇)alkylsulphonyl; (C₁-C₇)alkylsulphinyl; carbamoyl; N—(C₁-C₇)alkylcarbamoyl;N,N-di(C₁-C₇)alkylcarbamoyl; (C₁-C₇) alkylamino; di( C₁-C₇) alkylamino;a group —A—COOR_(f) in which R_(f) represents a hydrogen atom or a(C₁-C₇)alkyl group and A represents (C₁-C₇)alkylene, (C₂-C₇) alkenylene,(C₁-C₇)oxyalkylene in which the alkylene chain is linked to the groupCOORf or alternatively A is nothing; or a group —B—P(O)(OR_(x))(OR_(y))in which B takes one of the meanings given for A above and R_(x) andR_(y) independently take one of the meanings given for R_(f) above;

W represents —G—COORg in which G represents (C₁-C₇)alkylene,(C₂-C₇)alkenylene, (C₁-C₇)oxyalkylene in which the alkylene chain islinked to the group COOR_(g) or alternatively G is nothing, and R_(g)represents a hydrogen atom or a (C₁-C₇)alkyl group; or alternatively Wrepresents

—D—P(O)(OR_(z))(OR_(t)) in which D takes one of the meanings given abovefor G and R_(z) and R_(t) independently take one of the meanings givenabove for R_(g);

and the pharmaceutically acceptable salts thereof,

 it being understood that

(i) when R₂, R₃, R₅ and R₇ represent a hydrogen atom; X and Y representan oxygen atom; R₄ represents methyl; and R₆ represents a hydrogen atomor a methyl group, then R₁ and R, together with the carbon atom whichbears them, do not form any of the following divalent radicals:

and (ii) when R₄, R₅, R₆ and R₇ represent a hydrogen atom; X and Yrepresent O; and R represents pyridyl, piperidyl or substitutedpiperidyl; then R₁ does not represent optionally substituted phenyl.

Formula I encompasses all the types of geometrical isomers andstereoisomers of the compounds of formula:

The physiologically acceptable salts of the compounds of formula (I)comprise the salts formed with metals and in particular with alkalimetals, alkaline-earth metals and transition metals (such as sodium,potassium, calcium, magnesium or aluminum) or with bases such as aqueousammonia or secondary or tertiary amines (such as diethylamine,triethylamine, piperidine, piperazine or morpholine) or with basic aminoacids (such as lysine or arginine) or with osamines (such as meglumine)or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).

According to the invention, the term “alkyl” denotes a linear orbranched hydrocarbon-based radical such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl or heptyl. Whenthe alkyl group is substituted with one or more halogen atoms, itpreferably represents perfluoroalkyl and in particular pentafluoroalkyl.

The term “alkoxy” denotes an alkyl group as defined above linked to anoxygen atom. Examples of this are the methoxy, ethoxy, isopropyloxy,butoxy and hexyloxy radicals.

The term “cycloalkyl” denotes saturated hydrocarbon-based groups whichcan be mono- or polycyclic and comprise from 3 to 12 carbon atoms,preferably from 3 to 8. The groups more particularly preferred aremonocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl and cyclododecyl. The term “halogen” means a fluorine,chlorine, bromine or iodine atom.

The term “aryl” represents a mono- or bicyclic aromatichydrocarbon-based group comprising 6 to 10 carbon atoms, such as phenylor naphthyl.

The term “heterocycle” denotes a mono- or bicyclic ring of aromatic ornon-aromatic nature comprising 3 to 10 ring members, 1 to 4 of which areoccupied by identical or different hetero atoms chosen from oxygen,sulphur and nitrogen, such as, for example, aziridinyl, oxiranyl,oxazolyl, furyl, tetrahydrofuryl, benzothiazolyl, pyrimidinyl,pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl,phthalazinyl, purinyl, indolyl, chromenyl, chromanyl, isochromanyl andpyrrolyl radicals.

The term “heterocycle” preferably denotes thienyl, furyl or pyrrolyl.

The phthalamido (C₁-C₇)alkyl group preferably denotes the radical offormula:

When R represents (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₇)alkyl or aheterocycle, the aryl group and the heterocycle can be substituted witha (C₁-C₇)alkylene chain. In this case, the two free valencies of thesaid alkylene chain are linked to two members of the aryl group, or ofthe heterocycle, respectively. Denoting the aryl group or theheterocycle as C, the structure formed can be represented in thefollowing manner:

in which n′ represents 1, 2, 3, 4, 5, 6 or 7.

When R₁ represents a group —CONR₁₀R₁₁ in which R₁₀ and R₁₁ together forma chain —(CH₂)_(r)—, R₁₀, R₁₁ and the nitrogen atom which bears themtogether form a 5- to 7-membered nitrogen ring comprising an endocyclicnitrogen atom.

When R₂ or R₃ represents fluorenyl, it is preferably the 9-fluorenylgroup.

When R₂ and R₃ together form a —(CH₂)_(r1)— chain, R₂ and R₃ and thecarbon atom which bears them together preferably form a cyclopropylgroup.

The benzyl group may be mentioned as a preferred(C₆-C₁₀)aryl(C₁-C₇)alkyl group.

When R₂ and R₃ together form the group (a):

in which A₁, A₂, R₁₂ and R₁₃ are as defined above, A₁ and A₂ arehydrocarbon-based or heterocyclic rings comprising at least oneethylenic unsaturation >C═C< and bearing at least the radical R₁₂, orR₁₃, respectively, as substituent, but possibly bearing othersubstituents chosen from the radicals Z as defined above.

It is preferred for A₁ and A₂ to represent phenyl optionally substitutedwith one to four substituents Z.

It will be noted that the schematic representation of A₁ and A₂ givenabove means that A₁ and A₂ are linked to the same carbon atom (carbon 1)via carbon-carbon single bonds (bond 1-2, or 1-2′, respectively), thecarbon atom of the ring A₁, or of the ring A₂, respectively, engaged inthis bond (2, or 2′, respectively) being of sp² type, i.e. forming adouble bond with a neighbouring carbon atom, located in an a position(carbon 3, or 3′, respectively).

The substituent R₁₂ is located in any position on the ring A₁, andsimilarly R₁₃ is linked to the ring A₂ via any of the ring members ofA₂. However, it is preferred for R₁₂ and R₁₃ to substitute,respectively, the sp² carbons in the a position, i.e. the carbons oftype (3 and 3′) as represented in the above scheme.

According to the invention, preferred meanings of the group (a) are:

The term “acyl” means a (C₁-C₇)alkylcarbonyl radical and the term“acylthio” means a (C₁-C₇)alkylthiocarbonyl radical of formula:

According to the invention, the term “alkenylene” radical moreover meansa divalent hydrocarbon-based radical bearing one or more ethylenicdouble bonds, such as, for example, —CH═CH— or:

The “carbamoyl” radical denotes the monovalent radical of formula—CO—NH₂. The “(C₁-C₇)alkylcarbamoyl” radical denotes a carbamoyl radicalsubstituted with a C₁-C₇ alkyl group on the nitrogen atom, and the“di(C₁-C₇)alkylcarbamoyl” radical denotes a carbamoyl radicalsubstituted on the nitrogen atom with two C₁-C₇ alkyl groups.

The “(C₁-C₇)alkylamino” radical denotes an amino group substituted onthe nitrogen atom with a (C₁-C₇)alkyl radical and the“di(C₁-C₇)alkylamino” radical denotes an amino group substituted on thenitrogen atom with two (C₁-C₇)alkyl radicals.

U.S. Pat. No. 4,056,540 describes compounds such as4-phenyl-1,3-benzodioxane bearing a carboxylic function in position 2 ofthe benzodioxane ring, which have anticonvulsive or antiarrhythmicactivity.

More recently, [4H]-1,3-benzodioxine-2-carboxylic acids and estersendowed with hypolipaemiant activity have been described in Eur. J. Med.Chem. Ther., 1983, 67.

However, the benzodioxane structure of these compounds differs entirelyfrom the structure of the compounds of the invention.

Tetrahedron Asymmetry, vol. 3, No. 8, 1075-1086, 1992 describes theasymmetric synthesis of chiral ketals and in particular the synthesis ofcertain compounds of formula:

in which R₀ represents —COOCH₃ or —CH₂OH.

However, that document makes no reference at all to the pharmacologicalvalue of these compounds. In addition, J. Med. Chem., 1969, 51 describesanti-inflammatory compounds of 2-aryl-2-α-piperidyl-1,3-dioxane type.Among these compounds, those corresponding to one of the followingformulae are relatively close to the compounds of the invention:

in which R′ represents a hydrogen atom, a chlorine atom or a methoxygroup; R⁰ ₁ and R⁰ ₂ represent either a hydrogen atom, an alkyl group oran aryl group; and R⁰ ₃ is a methyl or methoxy group.

However, the anti-inflammatory activity of these compounds is in no waycomparable with the hypolipidaemic and hypoglycaemic activity of thecompounds of the invention.

Among the compounds of the invention, certain are preferred.

A first group of preferred compounds consists of the compounds offormula I as defined above for which X and Y represent an oxygen atom.

A second group of preferred compounds consists of the compounds offormula I in which R₄, R₅, R₆ and R₇ represent a hydrogen atom.

A third group of preferred compounds consists of the compounds offormula I in which:

R represents a hydrogen atom; a (C₁-C₇)alkyl group; a phthalamido(C₁-C₇)alkyl group; (C₃-C₁₂)cycloalkyl; a heterocycle as defined abovefor formula I; a (C₆-C₁₀)aryl group; or a (C₆-C₁₀)aryl(C₁-C₇)alkylgroup; it being understood that the aryl groups present in R and thesaid heterocycle are optionally substituted with one or moresubstituents chosen from a (C₁-C₇)alkylene chain; a halogen atom; aphenyl group; (C₁-C₇)alkyl optionally substituted with one or morehalogen atoms; (C₁-C₇)alkoxy; or a group —A—COORf in which A and Rf areas defined above for formula I;

R₁ represents a hydrogen atom; a (C₁-C₇)alkyl group; —(CH₂)_(t)—COORc inwhich t and Rc are as defined above for formula I;

R₂ and R₃ independently represent a hydrogen atom; a group (C₆-C₁₀)arylor (C₆-C₁₀)aryl(C₁-C₇)alkyl; the aryl groups present in R₂ and R₃optionally being substituted with one or more radicals chosen from ahalogen atom; a (C₁-C₇)alkyl group optionally substituted with one ormore halogen atoms; (C₁-C₇)alkoxy; N—(C₁-C₇)alkyl-carbamoyl;(C₁-C₇)alkylamino; nitro; cyano; and —A—COORf in which A and Rf are asdefined above for formula I;

or alternatively R₂ and R₃ together form the group (a) as defined abovefor formula I in which A₁ and A₂ represent a phenyl group; and R₁₂ andR₁₃ together form a chain —(CH₂)_(m)—E—(CH₂)_(n)— in which m, n and Eare as defined above for formula I, or a chain —CHR₁₄═CHR₁₅— in whichR₁₄ and R₁₅ are as defined above for formula I;

or alternatively R₂ and R₃ together form a chain —(CH₂)_(r1) in which r₁is an integer equal to 2, 3, 4 or 5.

A fourth group of preferred compounds consists of the compounds offormula I in which

R represents a hydrogen atom; a (C₁-C₇)alkyl group; (C₃-C₁₂)cycloalkyl;—(CH₂)_(p)—COOR_(b) in which p and R_(b) are as defined above forformula I; —(C₆-C₁₀)aryl or a heterocycle as defined above for formulaI; it being understood that the said aryl group and the said heterocycleare optionally substituted with one or more substituents chosen from ahalogen atom; a (C₁-C₇)alkyl group; (C₁-C₇)alkoxy; or —A—COORf in whichA and Rf are as defined above for formula I;

R₁ represents a (C₁-C₇)alkyl or —(CH₂)_(t)—COOR_(c) group in which t andR_(c) are as defined above for formula I; a group —CONR₁₀R₁₁ in whichR₁₀ and R₁₁ are as defined above for formula I;

R₂ and R₃ together form the group (a) as defined above for formula I inwhich A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain—(CH₂)_(m)—E—(CH₂)_(n)— in which m and n represent 0 and E represents abond.

Among these compounds, those for which

R represents a hydrogen atom; (C₁-C₄)alkyl; —(CH₂)_(p)—COOR_(b) in whichp represents 1, 2 or 3 and R_(b) represents a hydrogen atom or (C₁-C₄)alkyl; phenyl optionally substituted with a radical chosen from halogen,(C₁-C₄) alkyl, (C₁-C₄) alkoxy or —A—COORf in which A represents(C₁-C₄)alkylene or a bond and Rf represents H or (C₁-C₄)alkyl; furyl;thienyl; or pyrrolyl;

R₁ represents a (C₁-C₄)alkyl group; or alternatively —(CH₂)_(t)—COOR_(c)in which t represents 0, 1, 2, 3 or 4 and R_(c) represents a hydrogenatom or (C₁-C₄) alkyl;

R₂ and R₃ together form the group (a) as defined above for formula I, A₁and A₂ representing phenyl and R₁₂ and R₁₃ together forming a bond or a(C₁-C₄)alkylene chain

are particularly preferred.

A fifth group of preferred compounds consists of the compounds offormula I in which

R represents (C₆-C₁₀)aryl optionally substituted with a halogen atom;

R₁ represents —COOR_(c) in which R_(c) is as defined above for formulaI;

R₂ and R₃ together form the group (a) as defined above for formula I inwhich A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain—(CH₂)_(m)—E—(CH₂)_(n)— in which m and n represent 0 and E represents abond, O or S.

A sixth group of preferred compounds consists of the compounds offormula I in which

R represents (C₆-C₁₀)aryl optionally substituted with a halogen atom;

R₁ represents —COOR_(c) in which R_(c) is as defined above for formulaI;

R₂ and R₃ together form the group (a) as defined above for formula I inwhich A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain—CHR₁₄═CHR₁₅— in which R₁₄ and R₁₅ are as defined above for formula I.

A seventh group of preferred compounds consists of the compounds offormula I for which at least one of the radicals R or R₁ bears acarboxylic group optionally in esterified form or in the form of amide.Among these compounds, the preferred ones are those for which Rrepresents —(CH₂)_(p)—COOR_(b) [lacuna] and R_(b) are as defined abovefor formula I; or alternatively R represents (C₆-C₁₀)aryl or(C₆-C₁₀)aryl(C₁-C₇) alkyl in which the aryl group present in R issubstituted with a radical —A—COOR_(f) in which A and R_(f) are asdefined above for formula I; or alternatively R₁ represents—(CH₂)_(t)—COOR_(c) in which t and R_(c) are as defined above forformula I; or alternatively R₁ represents (C₆-C₁₀)aryl substituted with—G—COOR_(g) in which G and R_(g) are as defined above for formula I; oralternatively R₁ represents —CONR₁₀R₁₁ in which R₁₀ and R₁₁ are asdefined above for formula I.

Among this seventh group of preferred compounds, those satisfying atleast one of the following conditions are more particularly preferred:

X and Y represent an oxygen atom,

R₄ to R₇ represent a hydrogen atom;

only one of the groups R or R₁ bears a carboxylic group which isoptionally esterified or in the form of amide, the other being asdefined for the third group of preferred compounds above; and R₂ and R₃being as defined for the third group of preferred compounds;

only one of the groups R or R₁ bears a carboxylic group which isoptionally esterified or in the form of amide, the other being asdefined for the fourth group of preferred compounds above; and R₂ and R₃being as defined for the fourth group of preferred compounds:

When R bears a carboxylic group optionally in ester form, it preferablyrepresents phenyl substituted with —COOH; with —A—COOR_(f) in which Arepresents (C₂-C₅) alkenylene and R_(f) represents H or (C₁-C₄)alkyl; orwith (C₁-C₄)alkoxycarbonyl.

When R₁ bears a carboxylic group optionally in the form of ester oramide, it preferably represents —(CH₂)_(t)—COOR_(c) in which t is 0, 1,2, 3 or 4 and R_(c) is H or (C₁-C₄)alkyl; or alternatively —CONR₁₀R₁₁ inwhich R₁₀ and R₁₁ are as defined above for formula I, but in which R₁₀and R₁₁ do not together form a chain —(CH₂)_(r)—.

Examples of compounds of the invention are the following:

methyl 2-methyl-5,5-diphenyl[1,3]dioxane-2-carboxylate2-methyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-(4-methoxyphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(4-methoxyphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-(4-methylphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(4-methylphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl5,5-diphenyl-2-thiophen-2-yl[1,3]dioxane-2-carboxylate5,5-diphenyl-2-thiophen-2-yl[1,3]dioxane-3-carboxylic acid ethyl5,5-diphenyl[1,3]dioxane-2-carboxylate5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2,5,5-triphenyl[1,3]dioxane-2-carboxylate2,5,5-triphenyl[1,3]dioxane-2-carboxylic acid ethyl2-(4-fluorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(4-fluorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl5,5-diphenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,3]dioxane-2-carboxylateethyl 2-furan-2-yl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl2-(3-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(3-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-isopropyl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl2-phenethyl-5,5-diphenyl[1,3]dioxane-2-carboxylate2-phenethyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-biphenyl-4-yl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl2-(3,4-dichlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(3,4-dichlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic [lacuna]2-biphenyl-4-yl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2-[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]acetate2-[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]acetic acid ethyl2-cyclohexyl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl2-(5,5-diphenyl[1,3]dioxan-2-yl)benzoate2-(5,5-diphenyl[1,3]dioxan-2-yl)benzoic acid5,5-diphenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,3]dioxane-2-carboxylicacid 2-furan-2-yl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid2-(1-naphthyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid2-(1-naphthyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid2-isopropyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]methanol2-cyclohexyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]1-piperidyl ketone2-[(2-methyl-5,5-diphenyl[1,3]dioxan-2-yl)methyl]isoindole-1,3-dioneethyl5-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenyl]-3-methylpenta-2,4-dienoate5-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenyl]-3-methylpenta-2,4-dienoicacid2-(ethoxycarbonylmethylaminocarbonyl)-2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane2-carboxymethylaminocarbonyl-2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxaneethyl5,5-diphenyl-2-(4-trifluoromethylphenyl)-[1,3]dioxane-2-carboxylate2-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenoxy]-2-methylpropionic acid2-(4-trifluoromethylphenyl)-5,5-diphenyl[1,3]dioxan-2-ylcarboxylic acidethyl 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylate2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid ethyl2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylate2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylicacid ethyl2-(4-chlorophenyl)-5,5-bis(3-trifluoromethyl-phenyl)-[1,3]dioxane-2-carboxylate2-(4-chlorophenyl)-5,5-bis(3-trifluoromethylphenyl)-[1,3]dioxane-2-carboxylicacid ethyl2-(4-chlorophenyl)spiro[[1,3]dioxane-5,5′-5′H-dibenzo[a,d]cycloheptene]-2-carboxylate2-(4-chlorophenyl)spiro[[1,3]dioxane-5,5′-5′H-dibenzo[a,d]cycloheptene]-2-carboxylicacid 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9′-xanthene]-2-carboxylicacid 2-(4-chlorophenyl)spiro[1,3-dioxane-5,9′-xanthene]-2-carboxylicacid ethyl2-(4-chlorophenyl)-5-(9H-fluoren-9-yl)-[1,3]dioxane-2-carboxylate ethyl2′-(4-chlorophenyl)spiro[cyclobutane-1,5′-[1,3]dioxane]-2′-carboxylate2-(4-chlorophenyl)spiro[cyclobutane-1,5′-[1,3]dioxane]-2′-carboxylicacid 5,5-dibenzyl-2-(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acidmethyl 2-methylspiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-methylspiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid ethyl2-(2-methylspiro[[1,3]dioxane-5,9′-fluoren]-2-yl)acetate2-(2-methylspiro[[1,3]dioxane-5,9-fluoren]-2-yl)acetic acid methyl2-(2-methoxycarbonylethylspiro[[1,3]dioxane-5,9′-fluoren]-2-yl)acetate2-(2-carboxyethylspiro[[1,3]dioxane-5,9′-fluoren]-2-yl)acetic acidmethyl 4-(2-methylspiro[[1,3]dioxane-5,9′-fluoren]-2-yl)benzoate butylspiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylatespiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid methyl2-phenylspiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-phenylspiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid ethyl2-[4-methylphenyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate ethyl2-[4-methoxyphenyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-[4-methoxyphenyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acidethyl 2-[4-chlorophenyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-[4-chlorophenyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acidethyl 2-[2-thienyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-[2-thienyl]spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid2-(4-chlorophenyl)-5,5-diphenyl[1,3]oxazinane

Among these compounds, the following are particularly preferred:

ethyl 2-(4-chlorophenyl]-5,5-diphenyl[1,3]dioxane-2-carboxylate2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylate2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid ethyl2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid.

The compounds of the invention and those defined in points (i) and (ii)above can be prepared using any of the following processes.

In general, the compounds of formula I can be prepared by reaction of acompound of formula:

in which X, Y and R₂ to R₇ are as defined above for formula I, it beingunderstood that X or Y can also represent a nitrogen atom substitutedwith a function which is a precursor of the radical R_(a), with a ketoneof formula III:

RCO—R₁

in which R and R₁ are as defined above for formula I.

When, in formula I, X and Y are an oxygen atom, the processes A, B, C orD can be used.

Process A:

A diol of formula II

in which R₂ to R₇ are as defined for formula I, is reacted with acarbonyl derivative of formula III:

RCO—R₁

in which R and R₁ are as defined above for formula I, to give a compoundof formula I in which X and Y represent an oxygen atom.

The reaction used is a cyclization reaction. This reaction is carriedout under the standard conditions, either in the presence of a specificcatalyst as described in:

S. Fukusawa et al., Synlett, 1995, 1077.

G. C. G. Pals, J. Chem. Research, 1996, 426.

B. P. Bandgar, Synth. Commun., 1997, 27(4), 627.

K. Ishihara, Synlett, 1987, 839.

S. B. Lee, Synthesis, 1991, 368

or in the absence of a catalyst, as described in F. A. J. Meskens,Synthesis, 1981, 501.

H. Suemune et al., Chem. Pharm. Bull., 1990, 38(11), 3155.

The reaction is typically carried out in an aprotic solvent which formsan azeotrope with water, such as toluene, at a temperature of from 50 to150° C., better still from 90 to 120° C., in the presence of an excessof compound III. The molar ratio of compound III to the diol II willpreferably be between 1.1 and 2, for example between 1.3 and 1.7.

In order to increase the yields, it is recommended to react the diolwith the carbonyl compound in the presence of an acid catalyst such aspara-toluenesulphonic acid, while removing the water from the reactionmedium.

By way of example, the diol II may be reacted with the carbonylderivative III in the presence of 0.2 equivalent ofpara-toluenesulphonic acid at the reflux point of toluene in Dean-Starkapparatus for 6 to 8 hours.

As a variant, the reaction can be carried out in a halogenated aliphatichydrocarbon at a temperature of between 15 and 30° C. in the presence ofa Lewis acid. In this case, it is preferable for the molar ratio of thediol II to the carbonyl derivative III to range between 1.5 and 3,better still between 1.8 and 2.2.

By way of example, the diol II may be reacted with two equivalents ofthe derivative III in methylene chloride in the presence of oneequivalent of BF₃-etherate at room temperature for 12 to 48 hours.

Process B:

The compounds of formula I in which X and Y represent an oxygen atom canbe prepared by reacting an alkali metal or alkaline-earth metal salt ofa diol of formula II:

in which R₂ to R₇ are as defined for I above, with a dihalo compound offormula IV:

in which R and R₁ are as defined for I above and X represents a halogenatom.

The metal salt of the diol II used as reagent is a salt in which the twohydroxyl functions are salified, either with the same metal cation M²⁺of an alkaline-earth metal, or with two cations M⁺ of an alkali metal.It is preferred to carry out this reaction starting with an alkali metalsalt and in particular the sodium salt.

According to a preferred embodiment of the invention, the metal salt isformed in situ in the reaction medium by the action of a metal hydride(and for example a sodium hydride) on the diol of formula II.

The reaction of the salt of the diol II with compound IV is preferablycarried out in a polar aprotic solvent, such as an ether, at atemperature of between 15 and 30° C., preferably in a slight excess ofthe metal salt of the diol II.

In order to increase the yields, the process will be performed, forexample, in the presence of a crown ether as taught in Eur. J. Med.Chem. Chim. Ther. 1983, 67.

By way of example, 1.1 to 1.5 equivalents of the diol II are reactedwith compound IV in which X represents chlorine, in anhydrous dioxane assolvent, in the presence of sodium hydride and 18-crown-6 at roomtemperature (20° C.).

Process C:

The compounds of formula I in which X and Y represent an oxygen atom canalso be obtained by transacetalization reaction, and more specificallyby reacting the diol of formula II:

in which R₂ to R₇ are as defined above for formula I, with a ketal offormula V:

in which R and R₁ are as defined above for formula I and R₁₆ and R₁₇independently represent (C₁-C₇)alkyl or together form an alkylene chainof —(CH₂)_(r′)— type in which r′ is an integer equal to 4, 5 or 6.

This reaction is preferably carried out in an aprotic solvent whichforms an azeotrope with water, such as toluene, at a temperature ofbetween 80 and 150° C., for example at a temperature of between 90 and120° C. In order to increase the yields, it is desirable to perform theprocess in the presence of an excess of the diol of formula II (1.5 to 3equivalents, preferably 1.8 to 2.2 equivalents) and of an acid catalyst,such as para-toluenesulphonic acid.

Inspiration may be taken from J. Am. Chem. Soc. 1958, 80, 6613.

By way of example, two equivalents of the diol II are reacted with oneequivalent of compound V in the presence of 0.2 equivalent ofpara-toluenesulphonic acid in toluene maintained at reflux in Dean-Starkapparatus for 1 to 4 hours.

Process D:

The compounds of formula I in which X and Y represent an oxygen atom canbe synthesized from the diols of formula II by forming the intermediatesilyl derivatives according to reaction scheme 3 below:

Scheme 3

In this scheme, R and R₁ to R₇ are as defined for formula I and T₁ to T₃independently represent (C₁-C₄) alkyl.

According to this process, the disilyl derivative XI is prepared in aconventional manner. To do this, a person skilled in the art will refer,for example, to Tetrahedron 1994, 50, 42, 12143 and Chem. Lett. 1994,263. The disilyl derivative XI is preferably formed in situ in thepresence of the ketone III with which it reacts as it is formed. Thesetwo reactions are, in this case, preferably carried out in a polaraprotic solvent such as a halogenated aliphatic hydrocarbon. The molarratio of the ketone III to the diol II is preferably between 1.1 and 2,better still between 1.3 and 1.7. The silylation is carried out, forexample, by the action of an alkoxytrialkylsilane derivative (in whichthe alkyl parts are C₁-C₆). Preferably, a large excess ofalkoxytrialkylsilane is reacted with the diol II in the presence oftrifluoromethanesulphonate as catalyst. The molar ratio of thealkoxytrialkylsilane to the diol is, for example, between 2 and 6,better still between 3 and 5.

The temperature of the reaction medium is usually maintained between −40and −10° C.

By way of example, 1 equivalent of the ketone of [sic] III can bereacted with 1.3 equivalents of the diol II in anhydrous methylenechloride in the presence of 4 equivalents of isopropoxytrimethylsilaneat temperatures of about −20° C. and in the presence of 0.01 equivalentof trimethylsilyl trifluoromethane-sulphonate. The reaction time istypically about 3 hours.

The compounds of formulae III, IV and V are commercially available oreasily prepared from active compounds by carrying out standard methodsof organic chemistry.

For the synthesis of the acetals of formula V, a person skilled in theart may also refer to Synthesis 1983, 203.

Certain diols of formula II are described in the literature.

The diols of formula II can be obtained by carrying out any of theprocesses a), b) or c) below.

Process a).

The reaction scheme is represented below

In this scheme, A₁, A₂, R₁₂ and R₁₃ are as defined for formula I and Alkrepresents (C₁-C₆)alkyl.

To synthesize the epoxide VII from the ketone VIII, a person skilled inthe art may be inspired by the research described in:

J. Am. Chem. Soc. 1958, 80, 6389 or J. Am. Chem. Soc. 1931, 53, 205.

The ketone of formula VIII may, for example, be reacted with a compoundof formula IX:

in which Grp represents a leaving group (such as a chlorine atom) andAlk represents (C₁-C₆)alkyl in the presence of a base such as an alkalimetal hydride or an alkali metal alkoxide. The reaction is preferablycarried out in a polar aprotic solvent, such as an ether, at atemperature not exceeding 45° C. Since the reaction is exothermic incertain cases, the reaction medium should be cooed during the reaction.An excess of the compound IX relative to the compound VIII willadvantageously be used. A molar ratio of compound IX to compound VIII ofbetween 1.2 and 2 is appropriate.

By way of example, compound VIII will be reacted with 1.5 equivalents ofethyl chloroacetate in the presence of sodium hydride or sodium ethoxidein tetrahydrofuran, the reaction medium being maintained at atemperature below 45° C.

The aldehyde of formula VI is obtained from the epoxide VII in aconventional manner. Reference may be made, for example, to J. Med.Chem. 1968, 11, 380.

In general, the epoxide of formula VII is treated, in step 2, with abase such as potassium hydroxide at a temperature of between 15 and 120°C. For example, when Alk represents ethyl, the epoxide VII is refluxedin the presence of KOH for 8 hours.

In order to convert the aldehyde obtained of formula VI into the diol offormula II, the process will be performed as indicated in J. Med. 1969,12, 462 and J. Am. Chem. Soc. 1949, 2031.

By way of example, the diol II is obtained by treating the aldehyde VIwith formaldehyde in aqueous solution (from 1.2 to 2 equivalents offormaldehyde) in the presence of a base such as potassium carbonate(from 1 to 2 equivalents). The reaction temperature is advantageouslybetween 15 and 130° C., preferably between 80 and 120° C.

The ketones of formula VIII are commercially available or readilyprepared from commercial compounds.

Process b):

Another way of performing the process is illustrated in scheme 5 below.

Starting with the ketone VIII, the aldehyde VI is prepared by formingthe intermediate epoxide X by carrying out a process similar to the oneillustrated in J. Org. Chem. 1972, 35, 25, 4075. In order to convert thealdehyde VI into the diol of formula II, the process is performed asdescribed above for process a). Typically, the aldehyde VI is reacted inethanol with, for example, 0.2 mol of aqueous 37% formaldehyde solutionin the presence of a base which can be potassium carbonate (0.05 mol) atreflux for 20 hours. An amount of water representing about ⅕ of that ofethanol will advantageously be added to the medium.

Process c):

According to a third variant, the diol of formula II can be obtainedaccording to reaction scheme 6 below, in which Alk represents(C₁-C₆)alkyl and A₁, A₂, R₁₂ and R₁₃ are as defined above for formula I:

The ester XI can be metallated by the action of butyllithium intetrahydrofuran at a temperature of between −70 and −30° C. The reactionmixture is then treated with gaseous formaldehyde at a temperature offrom 0 to 25° C., which gives the α-hydroxymethyl derivative. Thiscompound is reduced by the action of a suitable reducing agent, in aconventional manner. Lithium aluminum hydride may be mentioned as areducing agent. In this case, the reduction is complete after two hours,the reaction medium being maintained at a temperature below 10° C.

Certain compounds of formula II are novel. According to one of itsaspects, the invention relates to the diols of formula II chosen from:

2,2-bis(4-fluorophenyl)propane-1,3-diol;

2,2-bis(3-trifluoromethylphenyl)propane-1,3-diol;

5-hydroxymethyl-5H-dibenzo[a,d]cyclohepten-5-ylmethanol; and

(9-hydroxymethyl-9H-xanthen-9-yl)methanol which are novel.

The esters of formula XI are commercial products or are readily preparedfrom commercial products.

Process E below allows the formation of the compounds of formula I inwhich X represents O and Y represents S.

Process E

According to this process, a compound of formula XII:

in which R₂ to R₇ are as defined above for formula I, is reacted withthe ketone of formula III

RCO—R₁  III

This reaction may be carried out by analogy with the processes describedin the following publications, which also illustrate the preparation ofthe compounds of formula XII:

E. L. Eliel et al., J. Am. Chem. Soc., 1962, 84, 2377

A. J. Liepa et al., Aust. J. Chem., 1986, 39, 1747

R. Caputo et al., Synthesis, 1987, 386

B. Burczyk et al., Synthesis, 1982, 831

F. E. Ziegler et al., Tetrahedron Lett., 1978, 31, 2767

A technique based on the one described in Caputo et al., Synthesis,1987, 386 consists in reacting the ketone III with the compound XII inthe presence of polystyryldiphenyliodophosphonium iodide in a polaraprotic solvent such as acetonitrile, at a temperature of between 10 and40° C., preferably at room temperature (about 20° C. ). Using anhydrousacetonitrile at 20° C., the reaction is complete within 30 minutes to 2hours.

For the synthesis of the compounds of formula I in which X and Y are agroup —NR_(a)—, process F below may be used.

Process F

According to this process, the diamine XIII:

in which R₂ to R₇ are as defined for formula I and R₁₈ and R₁₉independently have one of the meanings given for R_(a) in formula I orrepresent a precursor radical leading to any of these meanings, isreacted with the ketone of formula III:

RCO—R₁  III

The operating conditions for carrying out this reaction will be readilydetermined by a person skilled in the art, who may perform the process,for example, as taught in:

P. M. Hardy et al., J. Chem. Soc., Perkin Trans. 1, 1977, 1954

T. Araki et al., Macromolecules, 1995, 21(7), 1988

Carpentier et al., Tetrahedron, 1985, 41(18), 3803

R. Gosmini et al., Synlett, 1991, 111

A. Alexakis et al., Synlett, 1991, 625

M. Gray et al., Synlett, 1991, 729

T. Okawara et al., J. Chem. Soc., Chem. Commun., 1990, 20, 1385

Typically, the reaction of XIII with III is carried out in an aproticsolvent such as an aromatic hydrocarbon at a temperature of from 80 to150° C., preferably from 90 to 120° C.

The molar ratio of III to XIII may be between 1 and 5, better stillbetween 1 and 3. In order to increase the reaction kinetics and theyield, this reaction can advantageously be carried out in the presenceof an acid catalyst, such as para-toluenesulphonic acid.

By way of example, one equivalent of XIII is reacted with 1 to 3equivalents of the ketone III in refluxing toluene in the presence offrom 0.2 to 2.2 equivalents of para-toluenesulphonic acid in Dean-Starkapparatus for 6 to 24 hours.

When R₁₈ or R₁₉ represents a radical which is a precursor of R_(a), thereaction of XIII with III will be followed by a step of converting theresulting compound into the compound of formula I.

The operating conditions for this conversion will be readily determinedby a person skilled in the art using his or her general knowledge.

The compounds of XIII type can be synthesized, for example, according tothe schemes described in H. P. Kaufmann et al., Chem. Ber., 1959, 2810.

For the synthesis of the compounds of formula I in which X represents Cand Y represents —NR_(a)—, process G below may be carried out.

Process G

Compound XIV below:

in which R₂ to R₇ are as defined for I and R₂₀ has one of the meaningsgiven for R₁₇ above, is reacted with the ketone of formula III: RCO—R₁in which R and R₁ are as defined for formula I.

The compounds of formula I in which R_(a) is other than H can beobtained from the corresponding compounds of formula I in which R_(a) isH by N-alkylation. The N-alkylation will be carried out in a mannerwhich is known per se to those skilled in the art, for example by theaction of an alkyl iodide or a dialkyl sulphate.

The operating conditions for the reaction of compound XIV with theketone III are those conventionally used in the technique for this typeof reaction. They may be derived from any of the following publications:

W. Schneider et al., Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1966, 299,997

G. Bernath et al., Pharmazie, 1983, 38, 2, 89

E. D. Bergmann et al., J. Chem. Soc., 1963, 3736

E. Biekert et al., Chem. Ber., 1961, 1664

In general, the operating conditions prescribed in the case of process Fmay be suitable.

By way of example, the amino alcohol XIV can be reacted with 1 to 3equivalents of the ketone III in refluxing toluene in the presence offrom 0.2 to 1.2 equivalents of para-toluenesulphonic acid in Dean-Starkapparatus for 4 to 10 hours.

The amino alcohols XIV can be prepared, for example, according to theschemes described in C. A. Grob et al., Helv. Chem. Acta, 1972, 501.

The publications cited above also illustrate the preparation of theamino alcohols of formula XIV.

The compounds of formula I in which X and Y represent S may be preparedby carrying out process H below.

Process H:

According to this process, the dithiol of formula XV:

in which R₂ to R₇ are as defined for formula I, is reacted with theketone of formula III: RCO—R₁ in which R and R₁ are as defined above forI.

The process will preferably be performed in a polar aprotic solvent suchas an ether at a temperature of from 15 to 30° C., better still from 18to 25° C., in the presence of a slight excess of the ketone III.

The molar ratio of compound XV to compound III is usually between 1 and2, preferably between 1.3 and 1.7.

More generally, reference may be made to

I. Shahak et al., J. Chem. Soc. 1966, 1005

G. A. Olah et al., Synthesis, 1981, 282 for the implementation of thisreaction.

By way of example, compound XV is reacted with 1.2 equivalents of theketone III in dioxane at 20° C. until the reaction is complete (from 5minutes to 2 hours are generally sufficient).

The dithiols of formula XV are prepared in a manner which is known perse and exemplified in particular in J. Houk et al., J. Amer. Chem. Soc.1987, 6825-6836 and E. L. Eliet et al., J. Amer. Chem. Soc., 1976,3583-3590.

The hypolipidaemic and hypoglycaemic activity of the compounds of theinvention result from their capacity to activate the PPARα and PPARγtype receptors. The activation of the PPARα receptors has beenillustrated using rat primary hepatocytes in the case of the compound ofExample 4.

More specifically, the effects of the compounds of the invention on theexpression of genes involved in lipid metabolism (Acyl CoA oxidase) orlipid transport (apo A-I, apo C-III) were studied in the model of rathepatocytes in primary culture obtained according to a modification ofthe initial procedure of Berry and Friend (Berry M, Friend D. 1969. J.Cell. Biol. 43: 506-520) described previously (Berthou L, Saladin R,YaQoob P, Branellec D, Calder P, Fruchart J C, Denèfle P, Auwerx J,Staels B. 1995. Eur. J. Biochem.: 232, 179-187). These genes aremodulated in a coordinated manner by PPAR and thus represent goodmarkers of the activation of the PPARα mainly expressed in the hepatictissue (Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W; 1995.Endocrinology: 137, 354-366). The hepatocytes were isolated by “in situ”hepatic infusion of collagenase (Wistar rats whose weight ranges between200 and 250 g), homogenization of the tissue, filtration through Nylon,centrifugation at low speed and inoculation at a rate of 10⁷ cells perdish (if the viability estimated by the Trypan blue test exceeds 90%).The cells were stimulated from the start of inoculation (compoundsdissolved in DMSO) in L15 culture medium supplemented with 10% foetalcalf serum, 0.2% (mass/volume) of bovine serum albumin (BSA), 3 g/l ofglucose and 26 mM bicarbonate, 2 mM glutamine and antibiotics. Afterincubation for 24 hours at 37° C. in a humid atmosphere of 5% CO₂/95%air, the cells were lysed in guanidine thiocyanate solution, the RNAsextracted with phenol (pH4/chloroform, assayed by spectrophotometer,transferred onto a membrane (Dot blot, Northern blot) and hybridizedwith specific molecular probes according to the procedures describedpreviously (Staels B, Van Tol A, Andreu T, Auwerx J; 1992. Atherioscler.Thromb. 12: 286-294). The cDNA of the clone 36B4 coding for the human POacidic ribosomal phosphoprotein (Masiakowski P, Breathnach R, Bloch J,Gannon F, Krust A, Chambon P; 1982. Nucl. Acids Res. 10: 7895-7903),whose tissue expression is stable, was used as control probe.

The cDNA probes were labelled with ³²P using random primers by means ofthe kit sold by Boehringer Mannheim. The membranes were hybridized with1.5×10⁶ cpm/ml of each probe according to the procedure describedpreviously (Staels B, Van Tol A, Andreu T, Auwerx J; 1992. Atherioscler.Thromb. 12: 286-294). They were washed once in 0.5×SSC buffer and 0.1%SDS at room temperature for 10 min and twice in the same buffer at 65°C. for 30 min, and then autoradiographed (X-OMAT-AR film, Kodak). Theautoradiographs were analysed by densitometry (Biorad GS670densitometer).

The effects of the compound of Example 4 on the hepatic gene expressionwere studied.

The hepatic expression of the ACO gene is increased by a 24-hourtreatment with the compound of Example 4 (25 μM). This response istypical of the effects observed previously (Berthou L, Saladin R, YaQoobP, Branellec D, Calder P, Fruchart J C, Denèfle P, Auwerx J, Staels B.1995. Eur. J. Biochem.: 232, 179-187) (Staels B, Vu-Dac N, Kosykh V. A.,Saladin R, Fruchart J. C., Dallongeville J., Auwerx J.; 1995. J. Clin.Invest. 95: 705-712) when the hepatocytes are treated with fibrateswhich are ARα ligands and activators (Devchand P, Keller H, Peters J,Vasquez M, Gonzales F, Wahli W.; 1996. Nature; 384: 39-43). Theseresults suggest that the compounds of the invention act via PPARα.Similar results were reproduced in two independent experiments.

Expression of the mRNAs coding for the ACO genes in rat hepatocytes inprimary culture treated for 24 hours with the compound of Example 4 (25μm).

The values are expressed relative to the base value (%).

ACO Control 100 ± 0  Compound of 427 ± 63 Example 4

Activation of the PPARγ was similarly demonstrated in the case of thecompound of Example 4.

Analysis of the activation of PPARγ is based on the transfection of aDNA allowing the expression of a reporter gene (CAT (chloramphenicolacetyltransferase)) under the control of PPAR in cells which expressPPARγ. The reporter plasmid J3TkCAT described previously (Fajas L,Auboeuf D, Raspé E, Schoonjans K, Lefebvre A. M., Saladin R, Najib J,Laville M, Fruchart J. C., Deeb S, Vidal-Puig A, Flier J. Briggs M,Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272: 18779-18789)comprises three copies of the PPAR response element for human apo A-IIgene which are cloned upstream of the promoter for the thymidine kinasegene of the herpes simplex virus in the plasmid pBLCAT4 (Staels B,Vu-Dac N, Kosykh V. A., Saladin R, Fruchart J. C., Dallongeville J,Auwerx J.; 1995. J. Clin. Invest. 95: 705-712). The cells used are thegreen monkey CV1 cells and COS cells transformed by the SV40 virus andwhich express PPARγ (Forman B, Tontonoz P, Chen J, Brun R, Spiegelman B,Evans R.; 1995. Cell. 83: 803-812). These cells were inoculated at arate of 300,000 cells per dish (dishes 5 cm in diameter) and transfectedwith 500 ng of reporter DNA according to a process described previously(Fajas L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre A. M., Saladin R,Najib J. Laville M, Fruchart J. C., Deeb S, Vidal-Puig A, Flier J,Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272:18779-18789). After 5 to 6 hours, the cells were washed twice with PBSand incubated for 36 hours in fresh culture medium (DMEM) containing 10%foetal calf serum. After transfection, the cells were lysed and the CATactivity was measured according to the procedure described previously(Fajas L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre A. M., Saladin R,Najib J, Laville M, Fruchard J. C., Deeb S, Vidal-Puig A, Flier J,Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272:18779-18789). It is expressed relative to the control value.

The effects of the compound of Example 4 are given in FIG. 1.

The activity of the CAT reporter gene of Cos cells transfected with theJ3TkCAT construct is increased when these cells are incubated in thepresence of the compound of Example 4. On the other hand, when the Coscells are transfected with the pBLCAT4 plasmid lacking the PPAR responseelement, the compound of Example 4 is inactive.

In FIG. 1, T represents the control value for each reporter (TkCAT orJ3TkCAT).

In a final test, the hypolipidaemic and hypoglycaemic activity of thecompound of Example 4 was evaluated in db/db mice.

Two-month-old db/db mice were treated orally for 15 days with thecompound of Example 4 (100 mg/kg/day). Each study group comprises sevenanimals. After three days (D3) and 15 days (D15) of treatment,retro-orbital samples were taken after light anaesthesia and withoutfasting.

The following measurements were taken:

assay of the glycaemia (glucose oxidase) at D3 and D15 and of the lipidparameters on the sera at D15 (COBAS): triglycerides, total cholesterol(CHOL), HDL cholesterol (HDL-C) and free fatty acids (FFA) (assay kitfrom BioMérieux and Wako Chemicals).

The results obtained are given in the table below. The measurementsgiven in this table are average values±standard error.

% variation relative to Control Example 4 the control Glycaemia D3 33.19± 6.33  21.35 ± 5.67* −36 (mM) Glycaemia D15 39.19 ± 9.21   29.90 ±10.22* −24 (mM) Triglycerides 1.78 ± 0.54  1.07 ± 0.74* −40 D15 (mM)CHOL D15 (mM) 2.69 ± 0.36 2.60 ± 0.13  −3 HDL-C D15 (mM) 1.65 ± 0.321.64 ± 0.19  −1 FFA D15 (mM) 0.72 ± 0.20 0.52 ± 0.17 −27 *p < 0.05relative to the control in the Mann-Whitney test.

A subject of the invention is also a pharmaceutical compositioncomprising an effective amount of at least one active principle chosenfrom a compound of formula I as described above, a compound of formulaXVI:

in which R and R₁ together form one of the radicals:

R₂, R₃, R₅ and R₇ represent a hydrogen atom;

X and Y represent an oxygen atom;

R₄ represents a methyl; and

R₆ represents a hydrogen atom or a methyl group;

and a pharmaceutically acceptable salt of these compounds, incombination with at least one pharmaceutically acceptable vehicle.

These compositions can be administered orally in the form ofimmediate-release or controlled-release granules, gelatin capsules ortablets, intravenously in the form of an injectable solution,transdermally in the form of an adhesive transdermal device, or locallyin the form of a solution, cream or gel.

A solid composition for oral administration is prepared by adding afiller and, where appropriate, a binder, a crumbling agent, a lubricant,a dye or a flavour enhancer to the active principle and by shaping themixture into a tablet, a coated tablet, a granule, a powder or acapsule.

Examples of fillers include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, and examples ofbinders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose,methylcellulose, acacia, gum tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of lubricants include magnesium stearate,talc, polyethylene glycol, silica and hardened plant oils. The dye canbe any of those authorized for use in medicinal products. Examples offlavour enhancers include cocoa powder, mint in herbal form, aromaticpowder, mint in oil form, borneol and cinnamon powder. Needless to say,the tablet or granule can be suitably coated with sugar, gelatin or thelike.

An injectable form containing the compound of the present invention asactive principle is prepared, where appropriate, by mixing the saidcompound with a pH regulator, a buffer, a suspending agent, asolubilizing agent, a stabilizer, a tonicity agent and/or a preservingagent, and by converting the mixture into a form for intravenous,subcutaneous or intramuscular injection, according to a standardprocess. Where appropriate, the injectable form obtained can befreeze-dried by a standard process.

Examples of suspending agents include methylcellulose, polysorbate-80,hydroxyethylcellulose, acacia, powdered gum tragacanth, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilizing agents include castor oil solidified withpolyoxyethylene, polysorbate-80, nicotinamide, polyethoxylated sorbitanmonolaurate and the ethyl ester of castor oil fatty acid.

In addition, the stabilizer includes sodium sulphite, sodiummetasulphite and ether, while the preserving agent includes methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic],cresol and chlorocresol.

The invention is also directed towards the use of an active principlechosen from a compound of formula I as defined above, a compound offormula XVI as defined above, a compound of formula XVII:

in which

X and Y represent an oxygen atom;

R₄, R₅, R₆ and R₇ represent a hydrogen atom;

R represents pyridyl, piperidyl; pyridyl optionally substituted with oneor more radicals chosen from a radical Z as defined above for formula Iand a (C₁-C₇)alkylene chain; and piperidyl optionally substituted withone or more radicals chosen from a radical Z as defined above and a(C₁-C₇)alkylene chain; and

R₁ represents phenyl optionally substituted with one or more radicals Was defined above for formula I; and a pharmaceutically acceptable saltof these compounds, for the preparation of a medicinal product intendedto prevent or treat dyslipidaemia, atherosclerosis and diabetes.

The examples which follow illustrate the invention in a non-limitingmanner.

The following abbreviations are used in the proton nuclear magneticresonance (NMR) data: s for singlet, d for doublet, t for triplet, q forquartet, o for octet and m for multiplet. The chemical shifts δ areexpressed in ppm; m.p. represents the melting point and b.p. representsthe boiling point.

EXAMPLE 1 Methyl 2-Methyl-5,5-diphenyl[1,3]dioxane-2-carboxylate

A mixture of 22.8 g (0.1 M) of 2,2-diphenyl-1,3-propanediol and 100 g(0.98 M) of methyl pyruvate is brought to 70° C. in a 500 mlround-bottomed flask under a nitrogen atmosphere. 22.4 g (0.156 M) ofP₂O₅ are added portionwise. An exothermic reaction takes place and thetemperature rises to 98° C. The mixture is allowed to return to roomtemperature and is poured slowly into ice-cold water. This mixture isextracted with methylene chloride and the extracts are washed withsodium hydroxide and water. The extracts are concentrated and theresidue is chromatographed by flash chromatography (70 CH₂Cl₂/50cyclohexane eluent). The product is then recrystallized from 40 ml ofdiisopropyl ether. 7 g of a product of m.p. 116° C. are obtained.

EXAMPLE 2 2-Methyl-5,5-diphenyl[1,3]dioxane-2-carboxylic Acid

7 g of methyl 2-methyl-5,5-diphenyl[1,3]-dioxane-2-carboxylate arerefluxed in the presence of 2.6 g of NaOH in a mixture of 120 ml ofmethanol and 30 ml of water. At the end of the reaction, the medium isconcentrated and the solid obtained is dissolved in 300 ml of water.After acidification with HCl, the white solid formed is filtered off. Itis recrystallized from a mixture of 50 ml of cyclohexane and 50 ml ofdiisopropyl ether. 4.1 g of a product of m.p. 148-150° C. are obtained.

EXAMPLE 3 Ethyl2-(4-Chlorophenyl)-5,5-diphenyl[1,3]-dioxane-2-carboxylate

42.5 g (0.2 M) of ethyl 2-oxo-2-(4-chlorophenyl)acetate are placed in400 ml of CH₂Cl₂ in a 500 ml reactor. 22.8 g (0.1 M) of2,2-diphenylpropane-1,3-diol and then 14.2 g (0.1 M) of BF₃.Et₂O areadded. The mixture is left to react with stirring for 72 h at roomtemperature. The reaction mixture is taken up in NaHCO₃ solution. Theorganic phase is washed with saturated NaCl solution. After drying overNa₂SO₄ and concentration, a very thick oil is obtained. 150 ml ofisopropyl ether are added and a white precipitate forms. Afterfiltration, 30 g of product melting at 156-158° C. are obtained (yield:71%).

Examples R R1 m.p. ° C. NMR 1 CH₃ COOCH₃ 116 CDCl₃: 1.37(3H, s);3.72(3H,s); 4.14 (2H, d, J=11.8Hz); 4.49(2H, d, J=11.8 Hz); 6.88 to 7.35(10H,m) 2 CH₃ COOH 148-150 CDCl₃: 1.78(3H, s); 4.55(2H, d, J= 11.8Hz);4.87(2H, d, J=11.8Hz); 7.25 to 7.67(10H, m) 3

COOC₂H₅ 156-158 CDCl₃: 1.09(3H, t, J =7.1Hz); 4.1(2H, q, J=7.1Hz);4.35(2H, d, J=11.8Hz); 4.53 (2H, d, J=11.8Hz); from 7 to 7.2(12H, m);from 7.38 to 7.41 (2H, m). 4

COOH 244-246 DMSO d₆: 3.33(1H exchangeable with CF₃COOD); 4.35(2H, d,J=11.9Hz); 4.13 (2H, d, J=11.9Hz); 7.1 to 7.5(14H, m). 5

COOC₂H₅ 163 CDCl₃: 1.08(3H, t, J= 7.1Hz); 3.64 (3H, s); 4.08(2H, q,J=7.1Hz); 4.35 (2H, d, J=11.8Hz); 4.5(2H, d, J= 11.8Hz); from 6.7 to6.75(2H, m) from 7 to 7.2(10H, m); from 7.35 to 7.38(2H, m) 6

COOH 225 DMSO d₆: 3.73(3H, s); 4.33(2H, d, J=11.92Hz); 4.88 (2H, d,J=11.9Hz); from 6.88 to 6.91(2H, m); from 7.13 to 7.45 (12H, m) 7

COOC₂H₅ 151 CDCl₃: 1.36(3H; t, J= 7.1Hz); 2.47 (3H, s); 4.37(2H, q, J=7.1Hz); 4.64(2H, d, J=11.8Hz); 4.8 (2H, d, J=11.8Hz); from 7.28 to 7.48(12H, m); from 7.6 to 7.63(2H, m) 8

COOH 193 DMSO d₆: 2.02(3H, s); 4.10(2H, d, J=11.8 Hz); 4.64(2H, d, J=11.8Hz); from 6.89 to 7.2(14H, m) 9

COOC₂H₅ 190-191 CDCl₃: 1.3(3H, t, J= 7.1Hz); 4.32(2H, q, =7.1Hz);4.5(2H, d, J=11.8Hz); 4.71 (2H, d, J=11.8Hz); from 6.96 to 7(1H, m);from 7.2 to 7.4 (12H, m) 10

COOH 193 DMSO d₆: 4.16(2H, d, J=12Hz); 4.72(2H, d, J 32 12.0Hz); from6.82 to 7.36(13H, m) 11 H COOC₂H₅  60 CDCl₃: 1.27(3H, t, J= 7.1Hz); 4.18to. 4.37(4H, m); 4.87 (2H, d, J=11.6Hz); 5.21(1H, s); 7.18 to 7.55(10H,m) 12 H COOH 158-160 CDCl₃: 4.25(2H, d, J= 11.6Hz); 4.78(2H, d,J=11.6Hz); 5.13 (1H, s); 7.04 to 7.42 (10H, m) 13

COOC₂H₅ 182 CDCl₃: 1.17(3H, t, J= 7.1Hz); 4.26(2H, q, J=7.1Hz); 4.55(2H, d, J=11.8Hz); 4.71(2H, d, J=11.8 Hz); 7.29 to 7.70 (15H, m) 14

COOH 211-213 CDCl₃: 4.56 to 4.65 (4H, m); 7.22 to 7.62 (15H, m) 15

COOC₂H₅ 152 CDCl₃: 1.08(3H, t, J= 12Hz); 4.09(2H, q, J=7.1Hz); from 4.32to 4.36(2H, m); 4.53 (2H, d, J=11.9Hz); from 6.84 to 6.9(2H, m); from7.08 to 7.2 (10H, m); from 7.4 to 7.43(2H, m) 16

COOH 234-235 DMSO d₆: 4.42(2H, d, J=11.9Hz); 5.01 (2H, d, J=11.9Hz);from 7.21 to 7.61 (14H, m) 17

COOC₂H₅ 115-116 CDCl₃: 1.15 to 1.20 (15H, m); 1.57(4H, s); 4.19(2H, q,J= 7.1Hz); 4.42(2H, d, J=11.7Hz); 4.58 (2H, d, J=11.7Hz); 7.1 to7.3(12H, m); 7.4(1H, s) 18

COOC₂H₅ 163 CDCl₃: 1(3H, t, J= 7.1Hz); 4.12(2H, q, J=7.1Hz); 4.3(2H, d,J=11.7Hz); 4.43 (2H, d, J=11.7Hz); 6.2(1H, m); 6.4(1H, d); from 7 to7.14 (10H, m); 7.25(1H, d, J=0.7Hz) 19

COOC₂H₅ 145-150 CDCl₃: 1.43(3H, t, J= 7.1Hz); 4.44(2H, q, J=7.1Hz); 4.7(2H, d, J=11.8Hz) 4.9(2H, d, J =11.8 Hz); from 7.4 to 7.55 (12H, m);7.65 to 7.7 (1H, m); from 7.8 to 7.83(1H, m) 20

COOH 252 DMSO d₆: 3.3(1H, s); 4.3(2H, d, J=11.9 Hz); 4.9(2H, d, J=11.9Hz); from 7.1 to 7.46 (14H, m) 21

COOC₂H₅ 103 CDCl₃: 0.98(6H, d, J= 6.9Hz); 1.52(3H, t, J=7.1Hz); 2.17(1H, sept, J=6.9 Hz); from 4.43 to 4.5 (4H, m); 4.85(2H, d, J =11.9Hz);from 7 17 to 7.2(2H, m); from 7.37 to 7.52(6H, m); from 7.62 to 7.65(2H, m) 22

COOC₂H₅ 102 CDCl₃: 1.25(3H, t, J= 7.1Hz); 1.93 to 1.99(2H, m); 2.48 to2.54(2H, m); 4.17 to 4.27(4H, m); 4.62 (2H, d, J=11.5Hz); 6.93 to7.43(15H, m) 23

COOH 197-198 CDCl₃: 2.03 to 2.09 (2H, m); 2.46 to 2.60 (2H, m); 4.33(2H,d, J =11.8Hz); 4.69 (2H, d, J =11.8Hz); 6.87 to 7.57(15H, m) 24

COOC₂H₅ 209 CDCl₃: 1.31(3H, t, J= 7.1Hz): 4.32(2H, q, J=7.1Hz); 4.6 (2H,d, J=11.7Hz); 4.8(2H, d, J=11.7 Hz); from 7.05 to 7.75 (19H, m) 25

COOC₂H₅ 108 CDCl₃: 1.45(3H, t, J= 7.1Hz); 4.45(2H, q, J=7.1Hz); 4.69(2H, d, J=11.8Hz); 4.89(2H, d, J=11.8 Hz); 7.20 to 7.65 (12H, m);7.92(1H, d, J=1.7Hz) 26

COOH 217-219 DMSO d₆: 4.26(2H, d, J=11.8Hz); 4.83 (2H, d, J=11.8Hz);from 7.1 to 7.54(19H, m) ; 13.4 (1H, s, exchangeable with CF₃COOD) 27

COOH 261 DMSO d₆: 4.26(2H, d, J=11.8Hz); 4.83 (2H, d, J=11.8HZ); from7.1 to 7.54(19H, m); 13.4(1H, s, exchangeable with CF₃COOD) 28

CH₂— COOC₂H₅ Boiling point: b.p._(0.5) = 120.90 CDCl₃: 0.82(3H, t, J=7.1Hz); 2.54(2H, s); 3.64(2H, q, J= 7.1Hz); 3.95 to 4.02 (2H, m);4.4(2H, d, J= 11.6Hz); from 6.7 to 6.75(2H, m); from 6.96 to 7.34(12H,m) 29

CH₂COCH 227 DMSO d₆: 2.76(2H, s); 4.11(2H, d, J=11.5 Hz); 4.85 (2H, d,J= 11.57Hz); from 6.96 to 7.16(14H, m); 12.1 (1H, s, exchangeable withCF₃COOD) 30

COOC₂H₅ 170 CDCl₃: 1.1 to 1.3(5H, m); 1.47(3H, t, J= 7.1Hz); from 1.67to 1.9(6H, m); from 4.3 to 4.5(4H, m); 4.78 (2H, d, J=11.8Hz); from 7.1to 7.15(2H, m); from 7.29 to 7.47 (6H, m); from 7.56 to 7.59(2H, m) 31

H 102 CDCl₃: 1.25(3H, t, J= 7.1Hz); 4.2(2H, q, J=7.1Hz); 4.33(2H, d,J=11.4Hz); 4.71 (2H, d, J=11.4Hz); 6.35(1H, s); 6.96 to 7.70(14H, m) 32

H 174-176 CDCl₃: 4 46(2H, d, J= 11.4Hz), 4.85(2H, d, J=11.4 Hz); 6.51(1H, s); 7.07 to 7.53 (12H, m); 7.74(1H, d, J=7.8Hz); 7.97(1H, d,J=7.8Hz) 33

COOH 216-217 DMSO d₆: 1.34(6H, s); 1.37(6H, s): 1.8 (4H); 4.5(2H, d, J=11.8Hz); 5.1(2H, d, J=11.8Hz); from 7.33 to 7.7(13H, m) 34

COOH 187 CDCl₃: 4.75(2H, d, J= 11.6Hz); 4.82(2H, d, J=11.6Hz); 6.6 (1H,m); 6.8(1H, m); from 7.3 to 7.5 (10H, m); 7.66(1H, m); 8.5 (1Hexchangeable with CF₃COOD) 35

COOC₂H₅ 172 CDCL₃: 1.01(3H, t, J= 7.1Hz); 4.07(2H, q, J=7.1Hz); 4.57(2H, d, J=11.6Hz); 4.65(2H, d, J=11.6 Hz); 7.03 to 7.46 (13H, m);7.76(2H, m); 7.87(1H, d, J= 7.4Hz); 8.59(1H, m) 36

COOH 248 DMSO d₆: 4.8(2H, d, J=11.8Hz); 5.11(2H, d, J=11.8Hz); 7.2 to7.7(13H, m); 8.01 (3H, m); 8.75(1H, d, J=8.3Hz); 13.6(1H, exchangeablewith CF₃COOD) 37

COOH 137 CDCl₃: 1(6H, J=6.9 Hz); 2.2(1H, m); 4.5 (2H, d, J=11.9Hz);4.9(2H, d, J=11.9 Hz) from 7.2 to 7.22 (2H, m); from 7.4 to 7.5(6H, m);from 7.6 to 7.65 (2H, m) 38

CH₂OH 120-122 DMSO d₆: from 3.3 to 3.4(2H, m); 4(2H, d, J=11.4Hz);4.8(2H, d, J=11.4Hz); from 4.9 to 4.92(1H, m, exchangeable with D₂O);from 7 to 7.6 (1H, m) 39

COOH 240 DMSO d₆: from 1.03 to 1.24(5H, m); from 1.6 to 1.7(6H, m); 4.21(2H, d, J=11.6Hz); 4.9(2H, d, J=11.8 Hz); from 7.2 to 7.7(10H, m) 40

230-232 DMSO d₆: 1.0(2H, m); 1.4(4H, m); 3.3(2H, m); 3.5(2H, m); 4.4(2H, d, J=11.4Hz); 4.9(2H, d, J=11.4. Hz); 7.32-7.2(10H, m); 7.4-7.5(4H,m) 41

CH₃ 145 CDCl₃: 1.6(3H, s); 4.0(2H, s); 4.5(2H, d, J=11.8Hz); 4.7 (2H, d,J=11.8Hz); 6.3-6.8(10H, m); 7.0- 7.8(4H, m) 42

H 115-117 CDCl₃: 1.2(3H, m); 2.0(3H(Z), s); 2.3 (3H(E), s); 4.1(2H, m);4.3(2H, d, J= 10.7Hz), 4.8(2H, d, J=10.7Hz); 5.6(1H, s); 5.7(1H(Z), s);5.8(1H(E), s); 6.7- 6.8(2H, m); 7.0-7.5 (14H, m) 43

H 220-222 DMSO d₆: 1.4(3H, s, Z form); 2.3(3H, s, E form); 4.4(2H, d, J=11Hz); 5.0(2H, d, J= 11Hz); 5.7(1H, s); 6.0((1H, s); 7.0-7.6 (16H, m);8.3(1H, d, Z form, J=16Hz) 44

CONH— CH₂— COOC₂H₅ 195-197 CDCl₃: 1.15(3H, t, J= 7.1Hz); 3.9(2H, d,J=5.4Hz); 4.1(2H, q, J=7.1Hz); 4.4(2H, d, J=11.6Hz); 4.5(2H, d, J=11.6Hz); 6.9(1H, m); 7.3- 7.1(12H, m); 7.5(2H, d, J=8.7Hz) 45

CO(NH)— CH₂COOH 258-260 DMSO d₆: 4.0(2H, d, J= 6.02Hz); 4.8(2H, d,J=11.7Hz); 5.0 (2H, d, J=11.7.Hz); 7.4-7.7(14H, m); 8.9 (1Hexchangeable, t, J= 6.0Hz) 46

COOC₂H₅ 145 CDCl₃: 1.1(3H, t, J= 7.1Hz); 4.11(2H, q, J=7.1Hz); 4.38(2H,d, J=11.9Hz); 4.57 (2H, d, J=11.9Hz); 7 to 7 23(10H, m) 7.47(2H, d,J=8.4 Hz); 7.6(2H, d, J = 8.4Hz) 47 H

168-170 CDCl₃: 1.58(6H, s); 4.42(2H, d, J=11.5 Hz); 4.88(2H, d, J=11.5Hz); 5.63(1H 6.91 to 7.57(14H, m) 48

COOH 210 DMSO d₆: 4.37(2H, d, J=11.9Hz); 4.96 (2H, d, J=11.9Hz); 7.09 to7.45(10H, m); 7.65 to 7.5(4H, m); 13.7(1H, s, exchangeable with TFA)

EXAMPLE 42 Ethyl5-[4-(5,5-Diphenyl[1,3]dioxan-2-yl)-phenyl]-3-methylpenta-2,4-dienoate

The following are placed in a 250 ml reactor fitted with Dean-Starkapparatus: 70 ml of toluene, 3.5 g (0.011 M) of ethyl5-(4-diethoxymethylphenyl)-3-methylpenta-2,4-dienoate, 5.0 g (0.011 M)of 2,2-diphenylpropanediol and finally 0.5 g of para-toluenesulphonicacid.

The mixture is refluxed for 1 h while removing the first fractionsdistilled. After cooling to room temperature, the reaction medium iswashed with 5% NaHCO₃ solution. The organic phase is separated out aftersettling has taken place and dried over Na₂SO₄. After concentration todryness, a thick oil is obtained.

The product is purified by flash chromatography with a mixture of 95cyclohexane/5 ethyl acetate as eluent.

3.5 g of product are thus obtained in the form of a foam which isrecrystallized from diisopropyl ether to give 2.3 g of product meltingat 115-117° C.

EXAMPLE 52 Ethyl 3,3′-bis(4-Fluorophenyl)oxirane-2-carboxylate

23.6 ml (0.220 M) of ethyl chloroacetate and 30 g (0.137 M) of4,4′-difluorobenzophenone are introduced into 80 ml of tetrahydrofuranin a 500 ml round-bottomed flask under a nitrogen atmosphere. A total of8.8 g of 60% sodium hydride is added portionwise to this medium every 30minutes. At the end of the addition, an exothermic reaction takes placeduring which the reaction is maintained at 40-45° C. by an ice bath.After leaving overnight at room temperature, the medium is hydrolyzed byaddition of dilute hydrochloric acid and then extracted with ether.After concentration, 62 g of an orange-coloured oil are obtained, whichproduct is purified by flash chromatography (70 cyclohexane/30 CH₂Cl₂eluent). 34.7 g of a product which crystallizes slowly are thusobtained, and this product is finally triturated from 40 ml of pentane.A further flash chromatography (95 cyclohexane/5 diisopropyl ethereluent) gives 27.5 g of pure ester.

NMR (CDCl₃): 0.88 (3H, t, J=7.1 Hz); 3.81 (1H, s); 3.83 to 3.93 (2H, m);6.85 to 6.95 (4H, m); 7.11 to 7.16 (2H, m); 7.25 to 7.30 (2H, m).

2-bis(4-Fluorophenyl)ethanal

27.5 g of ethyl 3,3′-bis(4-fluorophenyl)-oxirane-2-carboxylate in 210 mlof ethanol are refluxed for 8 hours in the presence of 55 ml of KOH (at20% in water) in a 500 ml round-bottomed flask. The reaction medium isconcentrated and the residue is taken up in 600 ml of water. Aninsoluble material is removed by filtration and the filtrate isacidified with hydrochloric acid and extracted with ether. The oilobtained after concentration is treated (oil bath) at 150° C. for onehour. 17.5 g of 2-bis(4-fluorophenyl)ethanal are thus obtained.

NMR (CDCl₃): 4.88 to 4.89 (1H, m); 7.04 to 7.20 (8H, m); 9.89 to 9.90(1H, m)

2,2′-bis(4-Fluorophenyl)-1,3-propanediol

A mixture of 17.5 g of 2-bis(4-fluorophenyl)-ethanol, 16.1 ml (0.153 M)of 37% formaldehyde, 7.6 g of potassium carbonate, 18 ml of water and 70ml of ethanol is refluxed for 7 hours in a 250 ml round-bottomed flask.After concentration of the medium, the residue is taken up in 200 ml ofwater and extracted with methylene chloride, which is concentrated. 21.1g of an oil are obtained and this product is purified by flashchromatography (eluent: 98 methylene chloride/2 methanol). 17.8 g of2,2′-(4-fluorophenyl)-1,3-propanediol [sic] are thus obtained (m.p.=74°C.).

NMR (CDCl₃): 2.16 to 2.18 (2H, m, exchangeable with D₂O); 4.11 to 4.21(4H, m); 6.91 to 7.18 (8H, m).

Ethyl2-(4-Chlorophenyl)-5,5-bis(4-fluoro-phenyl)-(1,3]dioxane-2-carboxylate(Example 51)

1.7 g of para-toluenesulphonic acid in 120 ml of toluene are refluxedfor 30 minutes in a 250 ml round-bottomed flask fitted with Dean-Starkapparatus. 8 g (0.0302 M) of 2,2′-bis(4-fluorophenyl)-1,3-propanedioland 7 g (0.0332 M) of ethyl (4-chlorophenyl)-oxoacetate are added andthe mixture is refluxed for 8 hours. The reaction medium is cooled,diluted with 200 ml of ethyl ether, washed with normal sodium hydroxideand the organic phase is separated out after settling has taken place,dried and concentrated. The residue is washed with isooctane and thenrecrystallized from isopropyl ether. A white solid of m.p. 150° C. isthus obtained.

2-(4-Chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylicAcid (Example 52)

2.8 g of ethyl2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylateare refluxed for 7 hours in 60 ml of methanol and 15 ml of watercontaining 0.7 g of NaOH. After concentrating, the residue is dilutedwith water and stirred until a solution is obtained. This solution iswashed with ether and the aqueous phase is acidified with HCl. The solidformed is filtered off and washed with water and pentane. The product isrecrystallized from 100 ml of toluene. (m.p.=228-30° C.; weight obtained1.9 g).

EXAMPLE 54 Ethyl 3,3′-bis(3-Trifluoromethylphenyl)oxirane-2-carboxylate

5.9 g of 60% sodium hydride are introduced in 3 portions, every 30minutes, into a 500 ml round-bottomed flask under a nitrogen atmosphereand containing 16.2 ml (0.15 M) of ethyl chloroacetate, 29.9 g (0.0938M) of 3,3′-bis(trifluoromethyl)benzophenone and 80 ml oftetrahydrofuran, at 40° C. The mixture is left stirring for a further 2hours at 40° C. and then overnight at room temperature. The medium ishydrolysed with 50 ml of HCl and then extracted with ether. The extractsare washed with water, dried and concentrated. The oil obtained ispurified by flash chromatography (eluent: 95 cyclohexane/5 isopropylether). 31 g of the ethyl ester are obtained.

NMR (CDCl₃): 0.89 to 0.93 (3H, m); 3.90 to 3.98 (3H, m); 7.38 to 7.66(8H, m).

2-bis(3-Trifluoromethylphenyl)ethanal

A mixture of 31 g of ethyl3,3′-bis(3-trifluoromethylphenyl)oxirane-2-carboxylate and 56.7 ml ofaqueous 20% KOH solution in 210 ml of ethanol is refluxed for 8 hours.The reaction medium is concentrated and the residue is taken up in waterand washed with ether. The aqueous phase is acidified and extracted withether. The residue is heated on an oil bath at 150° C. for one hour. Thecrude product is purified by flash chromatography (eluent: 70 CH₂Cl₂/30heptane) to give 15.5 g of 2-bis(3-trifluoromethyl-phenyl)ethanal.

NMR (CDCl₃): 4.86 to 4.89 (1H, m); 7.06 to 7.88 (8H, m); 9.77 to 9.78(1H, m).

2-bis(3-Trifluoromethylphenyl)-1,3-propanediol

A mixture of 12.2 g of 2-bis(3-trifluoromethylphenyl)ethanal, 7.7 ml of37% formaldehyde, 3.5 g of potassium carbonate, 8.8 ml of water and 35ml of ethanol is refluxed in a 500 ml round-bottomed flask for 6 hours.The reaction medium is concentrated and the residue is diluted withwater and extracted with ether. After concentrating, the residue ispurified by flash chromatography (eluent: 98 CH₂Cl₂/2 MeOH). Aftertrituration from 20 ml of pentane, 5 g of2-bis(3-trifluoromethylphenyl)-1,3-propanediol are obtained (m.p.=70°C.).

NMR (CDCl₃): 2.35 (2H, m, exchangeable with D₂O); 4.26 (4H, m); 7.18 to7.48 (8H, m).

Ethyl2-(4-Chlorophenyl)-5,5′-bis(3-trifluoro-methylphenyl)-[1,3]dioxane-2-carboxylate(Example 53)

1.2 g of para-toluenesulphonic acid in 90 ml of toluene are refluxed ina 250 ml round-bottomed flask fitted with Dean-Stark apparatus. 4.9 g ofethyl (4-chlorophenyl)oxoacetate and 7.1 g of2-bis(3-trifluoromethylphenyl)-1,3-propanediol are added. Refluxing iscontinued for 8 hours. The reaction medium is cooled, diluted with 150ml of diethyl ether, washed with 1N sodium hydroxide and dried. Theresidue obtained is purified by flash chromatography (eluent: 95CH₂Cl₂/5 heptane). 2.8 g of product are obtained (m.p.=110° C.).

2-(4-Chlorophenyl)-5,5′-bis(3-trifluoromethyl-phenyl)-[1,3]dioxane-2-carboxylicAcid (Example 54)

2.8 g of the above ester are treated at reflux for 5 hours in 60 ml ofmethanol, 15 ml of water and 0.6 g of NaOH. The reaction medium isconcentrated and the residue is taken up in 100 ml of water. Afterwashing with ether, the aqueous phase is acidified with hydrochloricacid. It is extracted with ether, the extracts are concentrated and theproduct is recrystallized from toluene. 1.4 g of product ofm.p.=197-199° C. are obtained.

EXAMPLE 55 Diethyl 2-(9H-Fluoren-9-yl)malonate

16.3 g (0.051 M) of ethyl malonate in 300 ml of toluene are introducedinto a 500 ml reactor under a nitrogen atmosphere. 4.6 g (0.056 M) of60% NaH in oil are added portionwise at room temperature. Thetemperature rises to 32° C. The reaction medium is then maintained at80° C. for 15 minutes. A white broth forms.

A solution of 25 g (0.051 M) of 9-bromofluorene in 60 ml of toluene isadded at this temperature. The mixture is left to react for 8 h at 80°C. 100 ml of ice-cold water are added at a temperature below 20° C. Theorganic phase is separated out after settling has taken place and washedwith water. It is dried over Na₂SO₄ and concentrated to dryness. An oil(31 g) which crystallizes is obtained.

Recrystallization is carried out in 160 ml of diisopropyl ether to give23.7 g of a product melting at 71° C. (70% yield).

NMR (CDCl₃): 1.0 (3H, t, J=7.1 Hz); 3.9 (1H, d, J=5.5 Hz); 4.0 (2H, q,J=7.1 Hz); 4.6 (1H, d, J=5.5 Hz); 7.1-7.3 (4H, m); 7.5 (2H, d, J=7.4Hz); 7.7 (2H, d, J=7.4 Hz).

2-(9H-Fluoren-9-yl)propane-1,3-diol

200 ml of anaesthetic ether and then 4.5 g (0.118 M) of LiAlH₄ areplaced in a 500 ml reactor under a nitrogen atmosphere. A solution of9.6 g (0.0296 M) of diethyl 2-(9H-fluoren-9-yl)malonate in 100 ml ofanaesthetic ether is added at a temperature below 20° C. The mixture isleft to react for 2 h at room temperature and then refluxed for 2 h.

The reaction medium is cooled to 0° [lacuna] and 100 ml of water areadded cautiously. This mixture is acidified with dilute H₂SO₄ andextracted with ethyl acetate. The extracts are washed with water andthen concentrated to dryness, after drying over sodium sulphate. An oilis obtained which is recrystallized from 130 ml of isopropyl ether. 6.3g of a white solid melting at 101° C. are obtained (88% yield).

NMR (CDCl₃): 2.2 (2H, s, exchangeable with D₂O); 2.9 (1H, m); 3.8-4.0(4H, m); 4.3 (1H, d, J=2.7 Hz); 7.4-7.6 (4H, m); 7.7 (2H, d, J=7.4Hz);7.9 (2H, d, J=7.4 Hz).

Ethyl 2-(4-Chlorophenyl)-5-(9H-fluoren-9-yl)-[1,3]dioxane-2-carboxylate(Example 55)

The product is obtained by reacting the above diol with ethyl2-(4-chlorophenyl)-2-oxoacetate according to the method alreadydescribed, by refluxing in toluene in the presence ofpara-toluenesulphonic acid.

Examples R2 R3 R1 m.p. ° C. NMR 49

COOC₂H₅ 170 CDCl₃: 1.14(3H, t, J=7.1Hz); 4.1(2H, q, J=7.1Hz); 4.32 to4.50(4H, m); 6.98 to 7.46 (12H, m) 50

COOH 259-261 DMSO d₆: 4.54 (2H, d, J=11.9Hz); 5.12(2H, d, J=11.9Hz);7.45 to 7.71(12H, m); 13.8(1H, s, exchangeable with CF₃COOD) 51

COOC₂H₅ 150 CDCl₃: 1.27(3H, t, J=7.1hz); 4.35(2H, q, J=7.1Hz); 4.55(2H,d, J= 11.8Hz); 4.70 (2H, d, J=11.8 Hz); 7.11 to 7.75 (12H, m) 52

COOH 228-230 CDCl₃: 4.39 to 4.42(4H, m); 6.84 to 7.49 (12H, m) 53

COOC₂H₅ 110 CDCl₃: 1.16 (3H, t, J= 7.1Hz); 4.17 (2H, q, J=7.1 Hz);4.42(2H, d,nl J=11.8Hz) 4.56(2H, d, J= 11.8Hz); 7.18 to 7.54(12H, m) 54

COOH 197-199 CDCl₃: 4.69 (2H, d, J=11.6 Hz); 4.75(2H, d, J=11.6Hz); 7.47to 7.79 (12H, m) 55

H COOC₂H₅ 151 CDCl₃: 1.07 (3H, t, J= 7.1Hz); from 2.84 to 2.95(1H, m);from 3.82 to 3.95(5H, m); 4.07(2H, q, J= 7.1Hz); from 7.2 to 7.5(10H,m); 7.7(2H, d, J= 7.3Hz) 56

COOC₂H₅ 117 CDCl₃: 1.14 (3H, t, J= 7.1Hz); from 1.64 to 1.7(2H, m); from1.8 to 1.92(4H, m); 3.74(2H, d, J= 11.6Hz); 3.87 (2H, d, J=11.6 Hz);4.13(2H, q, J=7.1Hz); from 7.2 to 7.28(2H, m); from 7.47 to 7.5(2H, m)57

COOH 171 CDCl₃: 1.7 to 1.9 (6H, m); 3.84 (2H, d, J=3 Hz); 3.76(2H, d,J=11.3Hz); 7.28(2H, d, J= 7.6 Hz); 7.49 (2H, d, J=6.93 8.5(1H, s) 58

COOH 198-200 DMSO: 2.32 (2H, s); 2.72 (2H, s); 3.53 (4H, s); 6.88-7.40(14H, m)

Examples R R1 m.p. (° C.) NMR 59 —CH₃ —COOCH₃ 110 CDCl₃: 1.8(3H, s);3.65(2H, d, J=10 Hz); 3.95(3H, s) 4.45(2H, d, J=10 Hz); 7.2 to 8.4(m) 60—CH₃ —COOH 199-202 DMSO d₆: 1.7(3H, s); 3.5(2H, d, J=12 Hz); 4.4(2H, d,J= 12Hz); 7.2 to 8.4 (8H, m) 61 —CH₃ —CH₂— Eb/0.2 mm CCl₄: 1.3(3H, t);1.9 COOC₂H₅ Hg = (3H, s); 3.15(2H, s); 180-190 3.8 to 4.9(6H, m); 7.0 to8.0(8H, m) 62 —CH₃ —CH₂— 106-110 CDCl₃: 1.9(3H, s); COOH 3.2(2H, s); 4.1(4H, s); 7.1 to 8 (8H, m); 10.0(1H, exchangeable with D₂O) 63 —CH₂—CH₂—COOCH₅ 120 CDCl₃: 2.3 to 2.95 COOCH₃ (4H, m); 3.7(2H, d, J=10Hz); 3.8(3H, s); 4.0(3H, s); 4.45(2H, d, J= 10Hz); 7.2 to 8.4(8H, m) 64—CH₂—CH₂— —COOH 226-228 CDCl₃: 2.2 to 3.0 COOH (hemi- (4H, m); 3.65(2H,hydrate) d, J=11Hz); 4.6 (2H, d, J= Hz); 7.0 to 8.4 (8H, m); 10.9(2H,exchangeable with D₂O) 65

CH₃ 132-134 CDCl₃: 1.85(3H, s); 3.6(2H, d, J= 12Hz); 4.05 (3H, s);4.35(2H, d, J=12Hz); 6.8 to 8.5(12H, m) 66 H —COO— Eb/0.2 mm CCl₄: 0.8to 2.1 nbutyl Hg (7H, m); 3.8 to 170-195 4.16(6H, m); 5.25 m.p. = (1H,s); 7 to 8.5 80° C. (8H, m) 67 H —COOH 158-160 CDCl₃: 4.0(2H, d,J=10Hz); 4.45 92H, d, J=10 Hz); 5.5(1H, s) 6.9 to 8.4(8H, m); 10.4(1H,exchangeable with D₂O) 68

—COOCH₃ 204 CDCl₃: 3.85(3H, s); 3.95(2H, d, J= 12Hz); 4.4(2H, d,J=12Hz); 6.8 to 8.2(13H, m) 69

—COOH 193-195 CDCl₃: 4.05(2H, d, J=12Hz); 4.4 (2H, d, J=12 Hz); 7.0 to8.2 (13H, m); 9.2(1H, exchangeable with D₂O) 70

—COOC₂H₅ 152-154 CDCl₃: 1.1 to 1.6 (3H, m); 2.4(3H, s); 3.7 to 4.7 (6H,m); 7.1 to 8.1(12H, m) 71

—COOC₂H₅ 200 CDCl₃: 1.3(3H, t); 3.8 to 4.6(9H, 6.8 to 8.0 (12H, m) 72

—COOH 208 CDCl₃: 3.85(2H, d, J=12Hz); 3.85 (3H, s); 4.45(2H, d, J=12Hz);6.6 to 8.O (13H, 1H exchangeable with D₂O) 73

—COOC₂H₅ 178 DMSO d₆: 1.1(3H, t, J=7Hz); 3.6 to 4.8(6H, m); 7.0 to.8.2(12H, m) 74

—COOH 240-242 DMSO d₆: 3.75(2H, d, J=12Hz); 4.55(2H, d, J= 12Hz); 7.0 to8.4 (12H, m) 75

—COOC₅H₅ 130 CDCl₃: 1.45(3H, t, J=7Hz); 3.8 to 4.8(6H, m); 7.0 to8.2(11H, m) 76

—COOH 185-6 DMSO d₆: 3.85(2H, d, J=12 Hz); 4.45(2H, d, J= 12Hz); 7.0 to8.0 (11H, m); 10.0 (1H, exchangeable with D₂O)

EXAMPLE 77 Ethyl 9-Hydroxymethyl-9H-xanthene-9-carboxylate

A mixture of 1.5 g (5.9 mmol) of ethyl 9H-xanthene-9-carboxylate in 20ml of THF and 1.6 ml of DMPU under an inert atmosphere is cooled to −50°C. 4 ml (6.4 mmol) of BuLi (1.6 M in hexane) are added dropwise to thismedium with stirring, and the medium is then left stirring for 10minutes at −40° C. After allowing the reaction medium to warm to 10° C.,a flow of formaldehyde generated from 5.4 g (0.18 mol) of sublimedparaformaldehyde entrained by a stream of nitrogen is bubbled in. Afterstirring for 2 hours at room temperature, the suspension is dispersed in50 ml of water. The reaction medium is then extracted twice with 100 mlof ether. The combined organic phases are dried over Na₂SO₄. Afterevaporation, the residual oil is chromatographed on silica. Eluent:CH₂Cl₂. 1.1 g of a yellow oil are obtained (yield: 68%).

NMR (CDCl₃): 1.07 (3H, t, J=7.1 Hz); 2.38 (1H, t, J=7.4 Hz); 3.9 (2H, d,J=7.5 Hz); 4.1 (2H, q, J=7.1 Hz); 6.9-7.26 (8H, m).

(9-Hydroxymethyl-9H-xanthen-9-yl)methanol

1.1 g (3.8 mmol) of the ester prepared above in 10 ml of THF are addeddropwise to a mixture of 0.18 g (4.7 mmol) of LiAlH₄ dispersed in 30 mlof THF and cooled by a bath of cardice. After stirring for 2 hours atroom temperature, 20 ml of water are added cautiously to the reactionmedium. This mixture is then extracted twice with 100 ml of EtOAc. Thecombined organic phases are dried over Na₂SO₄. After evaporating todryness, 0.7 g of a yellow oil is obtained (yield: 75%).

NMR (CDCl₃): 1.36 (2H, m); 3.83 (4H, d, J=6.0 Hz); 6.95 (2H, t, J=7.9Hz); 6.96 (2H, d, J=7.9 Hz); 7.11 (2H, t, J=7.9 Hz); 7.32 (2H, d, J=7.9Hz).

Ethyl 2-(4-Chlorophenyl)spiro[1,3-dioxane-5,9′-xanthene]-2-carboxylate(Example 77)

0 .3 ml of BF₃.OEt₂ is added dropwise to a mixture of 1 g (4.7 mmol) ofethyl para-chlorophenyloxoacetate and 0.7 g of the diol prepared abovein 20 ml of CH₂Cl₂, stirred at room temperature. After stirring for 2hours at room temperature, the reaction medium is washed twice with 20ml of saturated NaHCO₃. The organic phase is dried over Na₂SO₄ and thenevaporated. The residual oil is chromatographed on a column of silicaand eluted with an EtoAc/cyclohexane mixture (1:9). 0.4 g of whitishcrystals is obtained and this product is recrystallized from acetone.0.32 g of white crystals is collected (yield: 25%). m.p.=131-132° C.

EXAMPLE 782-(4-Chlorophenyl)spiro[1,3-dioxane-5,9′-xanthene]-2-carboxylic Acid

A mixture of 0.09 g (0.2 mmol) of the ester prepared in Example 77,Example [sic], 0.5 g (9 mmol) of KOH, 20 ml of ethanol and 10 ml ofwater is stirred at reflux for 3 h. After cooling, the reaction mediumis acidified with concentrated HCl solution to pH=5 and extracted withethyl acetate. The combined organic phases are dried over Na₂SO₄ andthen evaporated. The residual oil is crystallized from a suitablesolvent. 0.06 g of white solid is isolated (yield=64%). m.p.=244-246° C.

EXAMPLE 79 (5-Hydroxymethyl-5H-dibenzo[a,d]cyclohepten-5-yl)methanol

A mixture of 11 g (0.05 mol) of5H-dibenzo[a,d]cycloheptene-5-carboxaldehyde (prepared according to L.SALISBURY, J. Org. Chem., 1972, 37, 4075), 66 ml of ethanol, 16.2 ml(0.2 mol) of aqueous 37% formaldehyde solution, 11 ml of water and 6.6 g(0.05 mol) of K₂CO₃ is refluxed for 20 hours. The reaction medium isthen poured into 1 liter of water with stirring and the mixture isextracted with CH₂Cl₂. The combined organic phases are dried over Na₂SO₄and evaporated. The residual mass is triturated from 60 ml of absoluteethanol and disperses as a beige-coloured solid, which is filtered offand dried. 5 g of product are obtained (yield: 40%).

m.p.=162-163° C. NMR (DMSO d₆): 3.9-5 (4H, m); 7 (2H, s); 7.2-7.5 (8H,m).

Ethyl2-(4-Chlorophenyl)spiro[1,3-dioxane-5,5′-5′H-dibenzo[a,d]cycloheptene]-2-carboxylate(Example 79)

A mixture of 2.9 g (15 mmol) of para-toluenesulphonic acid monohydrateand 500 ml of toluene in a reactor fitted with Dean-Stark apparatus isrefluxed until the water has been completely removed. 12.6 g (0.05 mol)of the diol prepared above and 16 g (75 mmol) of ethylpara-chlorophenyloxoacetate are then added. The mixture is refluxed for8 hours. After cooling, the reaction medium is washed with 300 ml ofsaturated aqueous NaHCO₃ solution and then with 300 ml of water. Theorganic phase is dried over Na₂SO₄ and then evaporated. The residual oilis chromatographed on a column of silica and eluted with a 5/95EtOAc/cyclohexane mixture. The product is then washed with isopropylether and dried. 3 g of a white solid are obtained (yield: 14%).m.p.=206-208° C.

EXAMPLE 802-(4-Chlorophenyl)spiro[1,3-dioxane-5,5′-5′H-dibenzo[a,d]cycloheptene]-2-carboxylicAcid

A mixture of 0.6 g (8 mmol) of potassium hydroxide, 17 ml of water, 70ml of ethanol and 1.8 g (4 mmol) of the ester prepared according toExample 12 is refluxed for 5 hours. The solvent is then evaporated off.The resulting gum is dissolved in 50 ml of water and this aqueous phaseis washed with ether and then acidified. The aqueous phase is extractedwith CH₂Cl₂. The combined organic phases are dried over Na₂SO₄ and thenevaporated. The residue is recrystallized from a suitable solvent. 1.1 gof a white solid are obtained (yield: 65%). m.p.>260° C.

Examples R2  R3 R1 m.p. ° C. NMR 77

COOEt 131-132 CDCl₃: 1.2(3H, t, J=7.1Hz); (2H, d, J=12.1 Hz); 4.22(2H,q, J=7.1Hz); 4.35 (2H, d, J =12.1 Hz); 6.88-7.09(4H, m); 7.13-7.25(2H,m); 7.33(2H, d, J= 8.6Hz); 7.53- 7.63(3H, m); 7.74 (1H, d, J=7.9 Hz) 78

COOH 244-246 DMSO d₆: 4.28(2H, d, J=12.1Hz); 4.47(2H, d, J= 12.1Hz);7.07- 7.47(3H, m); 7.78 (6H, m); 7.91-8.05 (3H, m) 79

COOC₂H₅ 206-208 CDCl₃: 1.1(3H, t, J=7Hz); 3.8 (1H, d, J=11.5 Hz);4.1(2H, q, J= 7Hz); 4.7(1H, d, J=11.5Hz); 4.8(1H, d, J= 11.5Hz); 5.2(1H,d, J=11.5Hz); 7 (2H, s); 7.2-7.5 (12H, m) 80

COOH >260 DMSO d₆: 3.5(1H, d, J=12Hz); 4.6 (1H, d, J=12 Hz); 4.7(1H, d,J= 12Hz); 5.5(1H, d, J=12 Hz); 7.1 (2H, s); 7.2-7.65 (12H, m); 13.5 (1H,s, exchangeable with CF₃COOD)

EXAMPLE 81 2-(4-Chlorophenyl)-5,5-diphenyl[1,3]oxazinane

This product is obtained by reacting 3-amino-2,2-diphenyl-1-propanolwith 4-chlorobenzaldehyde in refluxing toluene in the presence ofp-toluenesulphonic acid for 5 hours.

The usual work-up allows the product to be obtained:

m.p.=169-170° C.; NMR (CDCl₃): 1.72 (1H, exchangeable with D₂O); 3.69 to4.25 (3H, m); 4.9 to 4.96 (1H, m); 5.31 (1H, s); 7.19 to 7.6 (14H, m).

What is claimed is:
 1. Compound of formula I:

in which X and Y each represent an oxygen atom; R represents a hydrogen atom; a (C₁-C₇)alkyl group; a phthalmido(C₁-C₇)alkyl group; (C₃-C₁₂)cycloalkyl; a group —(CH₂)_(p)—COOR_(b) in which p is an integer from 0 to 6 and R_(b) represents a hydrogen atom or a (C₁-C₇)alkyl group; a (C₆-C₁₀)aryl group; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, S and N; a (C₆-C₁₀)aryl(C₁-C₇)alkyl group; it being understood that the aryl groups present in R and the said heterocycle are optionally substituted with one or more substituents chosen from a radical Z as defined below and a (C₁-C₇)alkylene chain; R₁ represents a hydrogen atom; a (C₁-C₇)alkyl group; (C₁-C₇)hydroxyalkyl; a (C₆-C₁₀)aryl group optionally substituted with one or more radicals W as defined below; a group —P(O)(OR₈)(OR₉) in which R₈ and R₉ are, independently, a hydrogen atom or a (C₁-C₇)alkyl group; a group —(CH₂)_(t)—COOR_(c) in which t is an integer from 0 to 6 and R_(c) represents a hydrogen atom or a (C₁-C₇)alkyl group; a group —CONR₁₀R₁₁ in which R₁₀ and R₁₁ independently represent a hydrogen atom, a (C₁-C₇)alkyl group, a group R_(d)O—CO—(C₁-C₇)alkyl in which R_(d) represents h or (C₁-C₇)alkyl, or alternatively R₁₀ and R₁₁ together form a —(CH₂)_(r)— chain in which r is an integer equal to 4, 5 or 6; R₂ and R₃ independently represent (C₆-C₁₀)aryl; (C₆-C₁₀)aryl(C₁-C₇)alkyl; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N, and S; or a fluorenyl group; the said aryl groups present in R₂ or R₃, the said fluorenyl optionally being substituted with one or more radicals Z as defined below; or alternatively R₂ and R₃ together form a chain —(CH₂)_(r1)— in which r1 is an integer equal to 2, 3, 4 or 5; or alternatively R₂ and R₃ together form the group (a):

 in which A₁ and A₂ independently represent (C₆-C₁₀)aryl or a 5- to 10-membered aromatic heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from N, O, and S, the said aryl group and the said heterocycle optionally bearing, in addition to the substituents R₁₂ and R₁₃, one or more other substituents chosen from the radicals Z as defined below; and in which R₁₂ and R₁₃ together form a chain —(CH₂)_(m)—E—(CH₂)_(n)— or CHR₁₄═CHR₁₅— in which m and n are, independently, an integer from 0 to 6; E represents a bond, O, S, —NR_(e)—, in which R_(e) represents a hydrogen atom or (C₁-C₇)alkyl or alternatively E represents a (C₁-C₇)alkylene or (C₆-C₁₀)arylene chain or a 3- to 10-membered divalent heterocyclic radical comprising 1 to 4 endocyclic hetero atoms chosen from O, N, and S; and R₁₄ and R₁₅ are chosen, independently from a hydrogen atom, (C₁-C₇)alkyl and (C₆-C₁₀)aryl; R₄, R₅, R₆ and R₇ independently represent a hydrogen atom; (C₁-C₇)alkyl; (C₆-C₁₀)aryl optionally substituted with one or more radicals Z as defined below; or a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S, the said heterocycle optionally being substituted with one or more radicals Z as defined below; is chosen from a halogen atom; a hydroxyl group; nitro; cyano; phenyl; phenyl(C₁-C₇)alkyl; trifluoromethoxy; (C₁-C₇)alkyl optionally substituted with one or more halogen atoms; (C₁-C₇)alkoxy; (C₁-C₇)alkylthio; (C₁-C₇)acylthio; (C₁-C₇)alkylsulphonyl; (C₁-C₇)alkylsulphinyl; carbamoyl; N—(C₁C₇)alkylcarbamoyl; N,N-di(C₁-C₇)alkylcarbamoyl; (C₁-C₇)alkylamino; di(C₁-C₇)alkylamino; a group —A—COOR_(d) in which R_(d) represents a hydrogen atom or a (C₁-C₇)alkyl group and A represents (C₁-C₇)alkylene; (C₂-C₇)alkenylene; (C₁-C₇)oxyalkylene in which the alkylene chain is linked to the group COOR_(f) or alternatively A is nothing; or a group —B—P(O)(OR_(x))(OR_(y)) in which B takes one of the meanings given for A above and R_(x) and R_(y) independently take one of the meanings for R_(f) above; W represents —G—COOR_(g) in which G represents (C₁-C₇)alkylene, (C₁-C₇)alkenylene, (C₁-C₇)oxyalkylene in which the alkylene chain is linked to the group COOR_(g) or alternatively G is nothing, and R_(g) represents a hydrogen atom or a (C₁-C₇)alkyl group; or alternatively W represents —D—P(O)(OR_(z))(OR_(c)) in which D takes one of the meanings given for G and R_(z) and R_(c) independently take one of the meanings given above for R_(g); and the pharmaceutically acceptable salts thereof,  it being understood that (i) when R₂, R₃, R₅ and R₇ represent a hydrogen atom, X and Y represent an oxygen atom; R₄ represents methyl; and R₆ represents a hydrogen atom or a methyl group, then R₁ and R, together with the carbon atom which bears them, do not form any of the following divalent radicals:

and (ii) when R₄, R₅, R₆ and R₇ represent a hydrogen atom; X and Y represent O; and r represents pyridyl, piperidyl or substituted piperidyl; then R₁ does not represent optionally substituted phenyl, with the proviso that at least one of the radicals R or R₁ bears a carboxylic group optionally in esterified form or in the form of amide.
 2. Compound of formula I according to claim 1, in which R₄, R₅, R₆ and R₇ represent a hydrogen atom.
 3. Compound of formula I according to claim 1, in which: R represents a hydrogen atom; a (C₁-C₇)alkyl group; a phthalamido (C₁-C₇)alkyl group; (C₃-C₁₂)cycloalkyl; a heterocycle as defined in claim 1; a (C₆-C₁₀)aryl group; or a (C₆-C₁₀)aryl(C₁-C₁)alkyl group; it being understood that the aryl groups present in R and the said heterocycle are optionally substituted with one or more substituents chosen from a (C₁-C₇)alkylene chain; a halogen atom; a phenyl group; (C₁-C₇) alkyl optionally substituted with one or more halogen atoms; (C₁-C₇)alkoxy; or a group —A—COORf in which A and Rf are as defined in claim 1; R₁ represents a hydrogen atom; a (C₁-C₇)alkyl group; —(CH₂)_(t)—COORc in which t and Rc are as defined in claim 1; R₂ and R₃ independently represent a hydrogen atom; a group (C₆-C₁₀)aryl or (C₆-C₁₀)aryl(C₁-C₇)alkyl; the aryl groups present in R₂ and R₃ optionally being substituted with one or more radicals chosen from a halogen atom; a (C₁-C₇)alkyl group optionally substituted with one or more halogen atoms; (C₁-C₇) alkoxy; N—(C₁-C₇)alkyl-carbamoyl; (C₁-C₇)alkylamino; nitro; cyano; and —A—COORf in which A and Rf are as defined in claim 1; or alternatively R₂ and R₃ together form the group (a) as defined in claim 1 in which A₁ and A₂ represent a phenyl group; and R₁₂ and R₁₃ together form a chain —(CH₂)_(m)—E—(CH₂)_(n)— in which m, n and E are as defined in claim 1, or a chain —CHR₁₄═CHR₁₅— in which R₁₄ and R₁₅ are as defined in claim 1; or alternatively R₂ and R₃ together form a chain —(CH₂)_(r1)— in which r₁ is an integer equal to 2, 3, 4 or
 5. 4. Compound of formula I according to claim 1, in which: R represents a hydrogen atom; a (C₁-C₇)alkyl group; (C₃-C₁₂)cycloalkyl; —(CH₂)_(p)—COOR_(b) in which p and R_(b) are as defined in claim 1; —(C₆-C₁₀)aryl or a heterocycle as defined in claim 1; it being understood that the said aryl group and the said heterocycle are optionally substituted with one or more substituents chosen from a halogen atom; a (C₂-C₇)alkyl group; (C₁-C₇)alkoxy; or —A—COORf in which A and Rf are as defined in claim 1; R₁ represents a (C₁-C₇)alkyl or —(CH₂)_(t)—COOR_(c) group in which t and R_(c) are as defined in claim 1; a group —CONR₁₀R₁₁ in which R₁₀ and R₁₁ are as defined in claim 1; R₂ and R₃ together form the group (a) as defined in claim 1 in which A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain —(CH₂)_(m)—E—(CH₂)_(n)— in which m and n represent 0 and E represents a bond.
 5. Compound of formula I according to claim 1, in which R represents (C₆-C₁₀)aryl optionally substituted with a halogen atom; R₁ represents —COOR_(c) in which R_(c) is as defined in claim 1; R₂ and R₃ together form the group (a) as defined in claim 1 in which A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain —(CH₂)_(m)—E—(CH₂)_(n)— in which m and n represent 0 and E represents a bond, O or S.
 6. Compound of formula I according to claim 1, in which R represents (C₆-C₁₀)aryl optionally substituted with a halogen atom; R₁ represents —COOR_(c) in which R_(c) is as defined in claim 1; R₂ and R₃ together form the group (a) as defined in claim 1 in which A₁ and A₂ represent phenyl; and R₁₂ and R₁₃ together form a chain —CHR₁₄═CHR₁₅— in which R₁₄ and R₁₅ are as defined in claim
 1. 7. Compound of formula I according to claim 1, chosen from ethyl 2-(4-chlorophenyl)-5,5-diphenyl[1,3]-dioxane-2-carboxylate, 2-(4-chlorophenyl)-5,5-diphenyl-[1,3]dioxane-2-carboxylic acid, ethyl 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylate, 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid, ethyl 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylate, 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9′-fluorene]-2-carboxylic acid.
 8. A process for preparing a compound of formula I, according to claim 1, comprising reacting a compound of formula:

in which X, Y and R₂ to R₇ are as defined in claim 1, with a carbonyl derivative of formula III: RCO—R₁  III in which R and R₁ are as defined in claim
 1. 9. A process for preparing a compound of formula I according to claim 1, in which X and Y each represent an oxygen atom, comprising reacting an alkali metal or alkaline-earth metal salt of a diol of formula II

in which R₂ to R₇ are as defined in claim 1, with a dihalo compound of formula IV

in which R and R₁ are as defined in claim 1 and X represents a halogen atom.
 10. A diol chosen from 2,2-bis(4-flurophenyl) propane-1,3 diol; 2,2-bis(3-trifluoromethylphenyl) propane-1,3 diol; 5-hydroxymethyl-5H-dibenzo[a,d]cyclohepten-5-ylmethanol; and (9-hydroxymethyl-9H-xanthen-9-yl)methanol.
 11. A pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and a compound of formula I as defined in (i) in claim 1, in combination with at least one pharmaceutically acceptable vehicle.
 12. A composition according to claim 11, in the form of an immediate-release tablet, a controlled-release tablet, a gelatin capsule, an injectable solution or a cream.
 13. A method for preventing or treating dyslipidaemia, atherosclerosis, and diabetes comprising administering to a patient an effective amount of a compound of formula I according to claim 1, and a compound of formula I as defined in (i) or (ii) in claim
 1. 14. A pharmaceutical composition according to claim 11, comprising an effective amount of at least one compound of formula I as defined in (i) in claim 12, in combination with at least one pharmaceutically acceptable vehicle.
 15. The method according to claim 13, comprising administering to a patient an effective amount of a compound of formula I as defined in (i) in claim
 13. 